chr16-89918089-C-G

Variant names:

• chr16-89918089-C-G
• rs3212356
• ENST00000570217.1:n.415C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The ENST00000570217.1(ENSG00000267048):​n.415C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 230,470 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: ENSG00000267048 ENST00000570217.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.123
• Publications: 0 publications found

Genes affected

ENSG00000267048 (HGNC:):

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 16-89918089-C-G is Benign according to our data. Variant chr16-89918089-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1695509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124903759	XM_047435031.1	c.1212+42C>G		intron_variant	Intron 3 of 3		XP_047290987.1
LOC124903759	XM_047435032.1	c.*244C>G		downstream_gene_variant			XP_047290988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000267048	ENST00000570217.1	n.415C>G		non_coding_transcript_exon_variant	Exon 3 of 3	4
MC1R	ENST00000555427.1	c.-409+42C>G		intron_variant	Intron 2 of 3	5		ENSP00000451760.1
MC1R	ENST00000639847.1	c.-409+42C>G		intron_variant	Intron 2 of 2	5		ENSP00000492011.1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 391 AN: 152242 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00912

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000448 AC: 35 AN: 78110 Hom.: 0 Cov.: 0 AF XY: 0.000388 AC XY: 14 AN XY: 36038

African (AFR) AF: 0.00854 AC: 31 AN: 3632

American (AMR) AF: 0.00 AC: 0 AN: 2428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4964

East Asian (EAS) AF: 0.00 AC: 0 AN: 11084

South Asian (SAS) AF: 0.00 AC: 0 AN: 672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 60

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 476

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 48260

Other (OTH) AF: 0.000612 AC: 4 AN: 6534

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152360 Hom.: 2 Cov.: 34 AF XY: 0.00239 AC XY: 178 AN XY: 74506

African (AFR) AF: 0.00914 AC: 380 AN: 41584

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.00287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.79
PhyloP100		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: -5

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

Other links and lift over

dbSNP: rs3212356; hg19: chr16-89984497;