16-89917962-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The XM_047435031.1(LOC124903759):c.1127T>C(p.Leu376Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 225,376 control chromosomes in the GnomAD database, including 41,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 29907 hom., cov: 34)

Exomes 𝑓: 0.53 ( 11560 hom. )

Consequence

LOC124903759
XM_047435031.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0740

Variant links:

Genes affected

LOC124903759 (HGNC:):

LOC124903759 links:

MC1R (HGNC:6929): (melanocortin 1 receptor) This intronless gene encodes the receptor protein for melanocyte-stimulating hormone (MSH). The encoded protein, a seven pass transmembrane G protein coupled receptor, controls melanogenesis. Two types of melanin exist: red pheomelanin and black eumelanin. Gene mutations that lead to a loss in function are associated with increased pheomelanin production, which leads to lighter skin and hair color. Eumelanin is photoprotective but pheomelanin may contribute to UV-induced skin damage by generating free radicals upon UV radiation. Binding of MSH to its receptor activates the receptor and stimulates eumelanin synthesis. This receptor is a major determining factor in sun sensitivity and is a genetic risk factor for melanoma and non-melanoma skin cancer. Over 30 variant alleles have been identified which correlate with skin and hair color, providing evidence that this gene is an important component in determining normal human pigment variation. [provided by RefSeq, Jul 2008]

MC1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-89917962-T-C is Benign according to our data. Variant chr16-89917962-T-C is described in ClinVar as [Benign]. Clinvar id is 321379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1 link	c.1127T>C	p.Leu376Pro	missense_variant	Exon 3 of 4		XP_047290987.1
LOC124903759	XM_047435032.1 link	c.*117T>C		3_prime_UTR_variant	Exon 3 of 3		XP_047290988.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
MC1R	ENST00000555427.1 link	c.-494T>C	5_prime_UTR_variant	Exon 2 of 4	5	ENSP00000451760.1	G3V4F0
MC1R	ENST00000639847.1 link	c.-494T>C	5_prime_UTR_variant	Exon 2 of 3	5	ENSP00000492011.1	Q01726
ENSG00000267048	ENST00000570217.1 link	n.288T>C	non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.594

AC:

90283

AN:

152042

Hom.:

29851

Cov.:

show subpopulations

Gnomad AFR

AF:

0.865

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.587

Gnomad ASJ

AF:

0.405

Gnomad EAS

AF:

0.917

Gnomad SAS

AF:

0.679

Gnomad FIN

AF:

0.518

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.548

GnomAD4 exome

AF:

0.526

AC:

38511

AN:

73216

Hom.:

11560

Cov.:

AF XY:

0.520

AC XY:

17653

AN XY:

33926

show subpopulations

African (AFR)

AF:

0.866

AC:

2864

AN:

3306

American (AMR)

AF:

0.624

AC:

1377

AN:

2208

Ashkenazi Jewish (ASJ)

AF:

0.404

AC:

1881

AN:

4656

East Asian (EAS)

AF:

0.913

AC:

9727

AN:

10652

South Asian (SAS)

AF:

0.653

AC:

406

AN:

622

European-Finnish (FIN)

AF:

0.547

AC:

AN:

Middle Eastern (MID)

AF:

0.534

AC:

238

AN:

446

European-Non Finnish (NFE)

AF:

0.418

AC:

18882

AN:

45154

Other (OTH)

AF:

0.508

AC:

3101

AN:

6108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

756

1511

2267

3022

3778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.594

AC:

90399

AN:

152160

Hom.:

29907

Cov.:

AF XY:

0.599

AC XY:

44577

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.865

AC:

35947

AN:

41540

American (AMR)

AF:

0.587

AC:

8983

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.405

AC:

1404

AN:

3470

East Asian (EAS)

AF:

0.917

AC:

4756

AN:

5184

South Asian (SAS)

AF:

0.678

AC:

3268

AN:

4822

European-Finnish (FIN)

AF:

0.518

AC:

5474

AN:

10574

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.425

AC:

28906

AN:

67954

Other (OTH)

AF:

0.551

AC:

1164

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1664

3327

4991

6654

8318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.459

Hom.:

29462

Bravo

AF:

0.611

Asia WGS

AF:

0.774

AC:

2694

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.7

(source)

DANN

Benign

0.79

PhyloP100

-0.074

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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16-89917962-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over