Variant 7-107710126-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000441.2(SLC26A4):c.2162C>A(p.Thr721Lys) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T721M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.03

Variant links:

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]

SLC26A4 links:

SLC26A4 (HGNC:):

SLC26A4 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a domain STAS (size 194) in uniprot entity S26A4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) 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 chr7-107710126-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 7-107710126-C-A is Pathogenic according to our data. Variant chr7-107710126-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1065206.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.2162C>A	p.Thr721Lys	missense_variant	19/21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.2162C>A	p.Thr721Lys	missense_variant	19/21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000644846.1 linkuse as main transcript	n.*64C>A		non_coding_transcript_exon_variant	8/10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000644846.1 linkuse as main transcript	n.*64C>A		3_prime_UTR_variant	8/10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000492030.2 linkuse as main transcript	n.377-29C>A		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1454998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724286

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

PM2: not found in gnomAD PM3_Strong: Pathogenic mutation confirmed in trans in two patients and phase unknown in one patient PP1: Segregation in one affected relative PP3: REVEL score > 0.7 PP4: Patient's phenotype highly specific for gene -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

.;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.5

D;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.89

Gain of methylation at T721 (P = 0.0354);Gain of methylation at T721 (P = 0.0354);

MVP

1.0

MPC

0.075

ClinPred

0.99

GERP RS

5.5

Varity_R

0.95

gMVP

0.92

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over