chr22-37977963-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_ModerateBP6BS2_Supporting

The NM_006941.4(SOX10):​c.601G>A​(p.Ala201Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SOX10
NM_006941.4 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.56
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17091891).
BP6
Variant 22-37977963-C-T is Benign according to our data. Variant chr22-37977963-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1961580.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS2
High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SOX10NM_006941.4 linkc.601G>A p.Ala201Thr missense_variant Exon 3 of 4 ENST00000396884.8 NP_008872.1 P56693-1A0A024R1N6
POLR2FNM_001301130.2 linkc.294-8191C>T intron_variant Intron 4 of 5 NP_001288059.1 B0QYL9
POLR2FNM_001363825.1 linkc.*38+5653C>T intron_variant Intron 5 of 5 NP_001350754.1
POLR2FNM_001301131.2 linkc.293+10793C>T intron_variant Intron 4 of 4 NP_001288060.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SOX10ENST00000396884.8 linkc.601G>A p.Ala201Thr missense_variant Exon 3 of 4 1 NM_006941.4 ENSP00000380093.2 P56693-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.0000243
AC:
6
AN:
246698
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
133992
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000270
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1459814
Hom.:
0
Cov.:
32
AF XY:
0.00000964
AC XY:
7
AN XY:
726330
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Jul 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 22, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2 -

not specified Uncertain:1
May 06, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: SOX10 c.601G>A (p.Ala201Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 1612016 control chromosomes. c.601G>A has been reported in the literature in at least one individual affected with hypogonadotropic hypogonadism and authors classified this variant as likely benign (Kallman syndrome) (e.g. Federici_2022). This report does not provide unequivocal conclusions about association of the variant with Waardenburg Syndrome Type 2E. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36531499). ClinVar contains an entry for this variant (Variation ID: 1961580). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.055
T
BayesDel_noAF
Benign
-0.090
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.27
T;T;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.73
.;T;T
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.17
T;T;T
MetaSVM
Uncertain
0.65
D
MutationAssessor
Benign
1.4
L;L;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
0.090
N;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.57
T;T;T
Sift4G
Benign
0.60
T;T;.
Polyphen
0.075
B;B;.
Vest4
0.28
MutPred
0.15
Gain of glycosylation at A201 (P = 0.0739);Gain of glycosylation at A201 (P = 0.0739);Gain of glycosylation at A201 (P = 0.0739);
MVP
0.58
MPC
0.85
ClinPred
0.070
T
GERP RS
4.5
Varity_R
0.070
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61756177; hg19: chr22-38373970; COSMIC: COSV62806701; COSMIC: COSV62806701; API