rs72950037

Variant names:

• chr3-69763693-G-A
• rs72950037
• NM_001354604.2:c.104+23992G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-69763693-G-A
• chr3-69763693-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001184967.2(MITF):​c.-53+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MITF NM_001184967.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9192
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 5 publications found

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]

MITF Gene-Disease associations (from GenCC):

• Tietz syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Waardenburg syndrome type 2A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• melanoma, cutaneous malignant, susceptibility to, 8

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Waardenburg syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Waardenburg-Shah syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13432837 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of 35, new splice context is: ttgGTcagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184967.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	NM_001354604.2	MANE Select	c.104+23992G>A		intron	N/A	NP_001341533.1	O75030-1
	MITF	NM_001354605.2		c.104+23992G>A		intron	N/A	NP_001341534.1
	MITF	NM_198159.3		c.104+23992G>A		intron	N/A	NP_937802.1	O75030-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MITF	ENST00000352241.9	TSL:1 MANE Select	c.104+23992G>A		intron	N/A	ENSP00000295600.8	O75030-1
	MITF	ENST00000956046.1		c.104+23992G>A		intron	N/A	ENSP00000626105.1
	MITF	ENST00000956043.1		c.104+23992G>A		intron	N/A	ENSP00000626102.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 8

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
PhyloP100		4.9
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.67

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

Other links and lift over

dbSNP: rs72950037; hg19: chr3-69812844;