7-116778957-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000245.4(MET):c.3522T>C(p.His1174His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,613,674 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

MET
NM_000245.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00005833

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -1.38

Publications

3 publications found

Variant links:

Genes affected

MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]

MET Gene-Disease associations (from GenCC):

hereditary papillary renal cell carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
papillary renal cell carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
autosomal recessive nonsyndromic hearing loss 97
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
osteofibrous dysplasia
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
arthrogryposis, distal, IIa 11
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 7-116778957-T-C is Benign according to our data. Variant chr7-116778957-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.38 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00218 (332/152336) while in subpopulation AFR AF = 0.00762 (317/41580). AF 95% confidence interval is 0.00693. There are 3 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MET	NM_000245.4 link	c.3522T>C	p.His1174His	splice_region_variant, synonymous_variant	Exon 17 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3 link	c.3576T>C	p.His1192His	splice_region_variant, synonymous_variant	Exon 17 of 21		NP_001120972.1
MET	NM_001324402.2 link	c.2232T>C	p.His744His	splice_region_variant, synonymous_variant	Exon 16 of 20		NP_001311331.1
MET	XM_011516223.2 link	c.3579T>C	p.His1193His	splice_region_variant, synonymous_variant	Exon 18 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MET	ENST00000397752.8 link	c.3522T>C	p.His1174His	splice_region_variant, synonymous_variant	Exon 17 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11 link	c.3576T>C	p.His1192His	splice_region_variant, synonymous_variant	Exon 17 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3 link	n.*1127T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3 link	n.*1127T>C		3_prime_UTR_variant	Exon 16 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00765

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000623

AC:

155

AN:

248840

AF XY:

0.000459

show subpopulations

Gnomad AFR exome

AF:

0.00814

Gnomad AMR exome

AF:

0.000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461338

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

130

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.00846

AC:

283

AN:

33458

American (AMR)

AF:

0.000581

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.0000279

AC:

AN:

1111860

Other (OTH)

AF:

0.000480

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152336

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00762

AC:

317

AN:

41580

American (AMR)

AF:

0.000523

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000871

Hom.:

Bravo

AF:

0.00252

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

May 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 12, 2022

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

May 17, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327)

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MET: BP4, BP7

Hereditary cancer-predisposing syndrome

Benign:2

Aug 06, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

May 28, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Renal cell carcinoma

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Papillary renal cell carcinoma type 1

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.064

(source)

DANN

Benign

0.59

PhyloP100

-1.4

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000058

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over