Genetic Variant HMMR:p.Gln548Arg (chr5-163483130-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001142556.2(HMMR):c.1643A>G(p.Gln548Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,612,622 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0092 ( 23 hom., cov: 33)

Exomes 𝑓: 0.00089 ( 18 hom. )

Consequence

HMMR
NM_001142556.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.19

Variant links:

Genes affected

HMMR (HGNC:5012): (hyaluronan mediated motility receptor) The protein encoded by this gene is involved in cell motility. It is expressed in breast tissue and together with other proteins, it forms a complex with BRCA1 and BRCA2, thus is potentially associated with higher risk of breast cancer. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Dec 2008]

HMMR links:

HMMR-AS1 (HGNC:49149): (HMMR antisense RNA 1)

HMMR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035706162).

BP6

Variant 5-163483130-A-G is Benign according to our data. Variant chr5-163483130-A-G is described in ClinVar as [Benign]. Clinvar id is 792019.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00918 (1398/152312) while in subpopulation AFR AF= 0.0307 (1275/41562). AF 95% confidence interval is 0.0293. There are 23 homozygotes in gnomad4. There are 655 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMMR	NM_001142556.2 link	c.1643A>G	p.Gln548Arg	missense_variant	Exon 14 of 18	ENST00000393915.9	NP_001136028.1	O75330-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMMR	ENST00000393915.9 link	c.1643A>G	p.Gln548Arg	missense_variant	Exon 14 of 18	1	NM_001142556.2	ENSP00000377492.4		O75330-3

Frequencies

GnomAD3 genomes

AF:

0.00918

AC:

1397

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0307

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00218

AC:

543

AN:

249050

Hom.:

AF XY:

0.00162

AC XY:

219

AN XY:

134866

show subpopulations

Gnomad AFR exome

AF:

0.0295

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000986

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000891

AC:

1301

AN:

1460310

Hom.:

Cov.:

AF XY:

0.000763

AC XY:

554

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.0298

Gnomad4 AMR exome

AF:

0.00246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00918

AC:

1398

AN:

152312

Hom.:

Cov.:

AF XY:

0.00879

AC XY:

655

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0307

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.0109

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00274

AC:

333

Asia WGS

AF:

0.00318

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

.;.;.;T

Eigen

Benign

0.078

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;.;.;M

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.075

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.32

T;T;T;T

Polyphen

0.57

P;P;B;P

Vest4

0.17

MVP

0.71

MPC

0.065

ClinPred

0.027

GERP RS

5.3

Varity_R

0.065

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over