rs145467740

Variant names:

• chr7-107689120-G-A
• rs145467740
• NM_000441.2:c.1069G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-107689120-G-A
• chr7-107689120-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. BS1 PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.1069G>A (p.Ala357Thr) variant in the SLC26A4 gene is 0.46% for African/African American chromosomes by gnomAD v4.1.0 (489/1613848 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL VCEP) for autosomal recessive hearing loss variants (BS1). The REVEL computational prediction analysis tool produced a score of 0.849, which is above the threshold necessary to apply PP3. The HL VCEP allows classification of variants as likely benign with only BS1 if no other criteria are in conflict. The HL EP reviewed the conflicting evidence (PP3) and felt it did not override the Likely Benign classification in​ this case as computational scores are error prone, especially when predicting pathogenicity. In summary, the HL VCEP classified this variant as likely benign. (BS1, PP3; Clingen Hearing Loss VCEP Specifications Version 2; 02/19/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132654/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:7
• Conservation: PhyloP100: 7.13
• Publications: 3 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: Likely_benign. The variant received -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1069G>A	p.Ala357Thr	missense	Exon 9 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.1069G>A	p.Ala357Thr	missense	Exon 9 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1069G>A	p.Ala357Thr	missense	Exon 8 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1069G>A	p.Ala357Thr	missense	Exon 9 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000434 AC: 109 AN: 251198 AF XY: 0.000339

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1461614 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 727118

African (AFR) AF: 0.00454 AC: 152 AN: 33466

American (AMR) AF: 0.000380 AC: 17 AN: 44714

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111802

Other (OTH) AF: 0.000348 AC: 21 AN: 60382

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74422

African (AFR) AF: 0.00532 AC: 221 AN: 41538

American (AMR) AF: 0.000982 AC: 15 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000313 Hom.: 1

Bravo AF: 0.00187

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	2	1	Pendred syndrome (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 4 (1)
-	-	1	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.70
MVP		0.97
MPC		0.036
ClinPred		0.028	T
GERP RS		4.7
Varity_R		0.66
gMVP		0.94
Mutation Taster		=54/46	polymorphism

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: rs145467740; hg19: chr7-107329565; COSMIC: COSV55918946; COSMIC: COSV55918946;