chr22-37972852-T-C

Variant names:

• chr22-37972852-T-C
• rs886057493
• NM_006941.4:c.*643A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_006941.4(SOX10):​c.*643A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOX10 NM_006941.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.337
• Publications: 0 publications found

Genes affected

SOX10 (HGNC:11190): (SRY-box transcription factor 10) This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development. Mutations in this gene are associated with Waardenburg-Shah and Waardenburg-Hirschsprung disease. [provided by RefSeq, Jul 2008]

POLR2F (HGNC:9193): (RNA polymerase II, I and III subunit F) This gene encodes the sixth largest subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. In yeast, this polymerase subunit, in combination with at least two other subunits, forms a structure that stabilizes the transcribing polymerase on the DNA template. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000362 (55/152122) while in subpopulation AMR AF = 0.0036 (55/15282). AF 95% confidence interval is 0.00284. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 55 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006941.4. 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
	SOX10	NM_006941.4	MANE Select	c.*643A>G		3_prime_UTR	Exon 4 of 4	NP_008872.1	P56693-1
	POLR2F	NM_001301130.2		c.293+5682T>C		intron	N/A	NP_001288059.1	B0QYL9
	POLR2F	NM_001363825.1		c.*38+542T>C		intron	N/A	NP_001350754.1	F8WC47

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX10	ENST00000396884.8	TSL:1 MANE Select	c.*643A>G		3_prime_UTR	Exon 4 of 4	ENSP00000380093.2	P56693-1
	SOX10	ENST00000360880.6	TSL:1	c.*643A>G		3_prime_UTR	Exon 5 of 5	ENSP00000354130.2	P56693-1
	SOX10	ENST00000698177.1		c.*643A>G		3_prime_UTR	Exon 5 of 5	ENSP00000513596.1	A0A8V8TM01

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152122 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1478 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 834

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 56

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1012

Other (OTH) AF: 0.00 AC: 0 AN: 60

GnomAD4 genome AF: 0.000362 AC: 55 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.000525 AC XY: 39 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00360 AC: 55 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000548

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	PCWH syndrome (1)
-	1	-	Waardenburg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	9.0
DANN	Benign	0.56
PhyloP100		-0.34

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

Other links and lift over

dbSNP: rs886057493; hg19: chr22-38368859;