rs375576481

Variant names:

• chr7-107694642-A-T
• rs375576481
• NM_000441.2:c.1363A>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. BA1 PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ile455Phe variant in the SLC26A4 gene is 3% (981/30778) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high frequency that is consistent with benign classification based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132664/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.0013 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (75 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:12
• Conservation: PhyloP100: 8.24
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. 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
	SLC26A4	NM_000441.2	MANE Select	c.1363A>T	p.Ile455Phe	missense	Exon 12 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1363A>T	p.Ile455Phe	missense	Exon 12 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1363A>T	p.Ile455Phe	missense	Exon 11 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1285A>T	p.Ile429Phe	missense	Exon 11 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0389

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00397 AC: 996 AN: 251092 AF XY: 0.00559

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00205 AC: 2991 AN: 1461222 Hom.: 75 Cov.: 30 AF XY: 0.00299 AC XY: 2173 AN XY: 726962

African (AFR) AF: 0.0000896 AC: 3 AN: 33464

American (AMR) AF: 0.0000447 AC: 2 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0329 AC: 2835 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111458

Other (OTH) AF: 0.00224 AC: 135 AN: 60366

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0389 AC: 188 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00435 AC: 528

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	1	2	Pendred syndrome (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 4 (1)
-	-	1	Microcephaly 5, primary, autosomal recessive (1)
-	-	1	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.011	T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	2.0	M
PhyloP100		8.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.89
Sift	Benign	0.19	T
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.95
MVP		0.95
MPC		0.073
ClinPred		0.12	T
GERP RS		5.7
Varity_R		0.52
gMVP		0.82
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs375576481; hg19: chr7-107335087; COSMIC: COSV55914217;