NM_000441.2:c.1229C>T

Variant names:

• chr7-107690203-C-T
• rs111033220
• NM_000441.2:c.1229C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1_Strong PS3_Supporting PP4 PP3 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VeryStrong; PMID:25372295, 23638949, 25468468, 24338212, 25394566, 19786220, 19017801, 27541434, 21366435, 17309986, 24007330, 24224479, 21961810, 2844304, 19509082, 15811013). The p.Thr410Met variant in SLC26A4 has been reported to segregate in an autosomal recessive pattern with hearing loss in at least 7 family members (PP1_Strong; PMID:19017801, 9618167, 15811013). Computational prediction tools and conservation analysis suggest that the p.Thr410Met variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA or Mondini malformation (PP4; PMID:15355436, 15811013). The allele frequency of the p.Thr410Met variant in the SLC26A4 gene is 0.062% (19/30782) of South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VS, PP1_S, PP3, PS3_P, PM2_P, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261403/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17 O:1
• Conservation: PhyloP100: 4.03
• Publications: 134 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

ENSG00000300331 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1229C>T	p.Thr410Met	missense	Exon 10 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.1229C>T	p.Thr410Met	missense	Exon 10 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1229C>T	p.Thr410Met	missense	Exon 9 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1229C>T	p.Thr410Met	missense	Exon 10 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 250840 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1459536 Hom.: 1 Cov.: 29 AF XY: 0.000172 AC XY: 125 AN XY: 726190

African (AFR) AF: 0.0000898 AC: 3 AN: 33404

American (AMR) AF: 0.000112 AC: 5 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.000706 AC: 28 AN: 39682

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86220

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1109972

Other (OTH) AF: 0.0000829 AC: 5 AN: 60290

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000914 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Autosomal recessive nonsyndromic hearing loss 4 (5)
4	-	-	not provided (4)
4	-	-	Pendred syndrome (4)
2	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)
1	-	-	Hearing loss, autosomal recessive (1)
1	-	-	Monogenic hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.076
ClinPred		0.58	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.95
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111033220; hg19: chr7-107330648; COSMIC: COSV55915451; COSMIC: COSV55915451;