rs1553704086

Variant names:

• chr3-69951856-G-A
• rs1553704086
• NM_001354604.2:c.925G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-69951856-G-A
• chr3-69951856-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001354604.2(MITF):​c.925G>A​(p.Glu309Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.64

Genes affected

MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76
• PP5: Variant 3-69951856-G-A is Pathogenic according to our data. Variant chr3-69951856-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 545452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2	c.925G>A	p.Glu309Lys	missense_variant	Exon 7 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.604G>A	p.Glu202Lys	missense_variant	Exon 6 of 9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.925G>A	p.Glu309Lys	missense_variant	Exon 7 of 10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.604G>A	p.Glu202Lys	missense_variant	Exon 6 of 9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tietz syndrome;C1860339:Waardenburg syndrome type 2A Pathogenic:1

Jun 01, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Waardenburg syndrome type 2A Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with COMMAD syndrome (MIM#617306), Tietz albinism-deafness syndrome (MIM#103500), Waardenburg syndrome type 2A (MIM#193510), Waardenburg syndrome/ocular albinism, digenic (MIM#103470). Dominant negative has also been reported as a likely disease causing mechanism (PMID: 27889061). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 27759048). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified as likely pathogenic by a clinical laboratory in ClinVar. (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed to segregate in three affected individuals of one VCGS internal family with deafness, one of these individuals also had a white forelock. However, there is not enough segregation in this family to meet our criteria to consider this as pathogenic evidence. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D;.;.;.;.;T;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D;D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;.;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.;D;D;.
Vest4		0.61
MutPred		0.31		Gain of MoRF binding (P = 0.0055);.;Gain of MoRF binding (P = 0.0055);.;.;.;.;.;.;.;
MVP		0.91
MPC		0.38
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs1553704086; hg19: chr3-70001007;