rs3212355

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.1135C>T(p.Pro379Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 226,752 control chromosomes in the GnomAD database, including 119 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 111 hom., cov: 34)

Exomes 𝑓: 0.0041 ( 8 hom. )

Consequence

LOC124903759
XM_047435031.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.166

Publications

10 publications found

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=-0.81).

BP6

Variant 16-89917970-C-T is Benign according to our data. Variant chr16-89917970-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 321380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1 link	c.1135C>T	p.Pro379Ser	missense_variant	Exon 3 of 4		XP_047290987.1
LOC124903759	XM_047435032.1 link	c.*125C>T		3_prime_UTR_variant	Exon 3 of 3		XP_047290988.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
ENSG00000267048	ENST00000570217.1 link	n.296C>T	non_coding_transcript_exon_variant	Exon 3 of 3	4
MC1R	ENST00000555427.1 link	c.-486C>T	5_prime_UTR_variant	Exon 2 of 4	5	ENSP00000451760.1	G3V4F0
MC1R	ENST00000639847.1 link	c.-486C>T	5_prime_UTR_variant	Exon 2 of 3	5	ENSP00000492011.1	Q01726

Frequencies

GnomAD3 genomes

AF:

0.0218

AC:

3325

AN:

152252

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0764

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00752

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0119

GnomAD4 exome

AF:

0.00413

AC:

307

AN:

74382

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

131

AN XY:

34436

show subpopulations

African (AFR)

AF:

0.0723

AC:

245

AN:

3390

American (AMR)

AF:

0.00579

AC:

AN:

2244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4750

East Asian (EAS)

AF:

0.00

AC:

AN:

10744

South Asian (SAS)

AF:

0.00

AC:

AN:

630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00222

AC:

AN:

450

European-Non Finnish (NFE)

AF:

0.0000871

AC:

AN:

45912

Other (OTH)

AF:

0.00711

AC:

AN:

6192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0219

AC:

3330

AN:

152370

Hom.:

111

Cov.:

AF XY:

0.0216

AC XY:

1611

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0763

AC:

3174

AN:

41590

American (AMR)

AF:

0.00751

AC:

115

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68040

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

151

302

452

603

754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0176

Hom.:

Bravo

AF:

0.0245

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 5

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:1

Mar 24, 2019

GeneDx

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

-0.81

CADD

Benign

5.0

(source)

DANN

Benign

0.94

PhyloP100

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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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rs3212355

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