rs201660407

chr7-107690236-A-Cchr7-107690236-A-Gchr7-107690236-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1262A>C(p.Gln421Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,550,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q421R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.16

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107690236-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 430229.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=3, Pathogenic=1}.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 7-107690236-A-C is Pathogenic according to our data. Variant chr7-107690236-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1262A>C	p.Gln421Pro	missense_variant, splice_region_variant	10/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1262A>C	p.Gln421Pro	missense_variant, splice_region_variant	10/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250686 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1398332 Hom.: 0 Cov.: 24 AF XY: 0.00000572 AC XY: 4 AN XY: 699612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000474

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000927 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000556159 ) and different missense changes at the same codon (p.Gln421Arg, p.Gln421Leu/ ClinVar ID: VCV000430229 , VCV000691513 ) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23918157). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 27, 2023	- -
Likely pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -

Pendred syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 421 of the SLC26A4 protein (p.Gln421Pro). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with SLC26A4-related conditions (PMID: 17718863, 23918157, 24224479, 28964290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 556159). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.97		Gain of methylation at K419 (P = 0.0763);Gain of methylation at K419 (P = 0.0763);
MVP		0.98
MPC		0.076
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs201660407; hg19: chr7-107330681;