rs397516423

Variant names:

• chr7-107701947-T-C
• rs397516423
• NM_000441.2:c.1924T>C

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 3P and 4B. PM3_Supporting BS1 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.1924T>C variant in SLC26A4 is a missense variant predicted to cause the substitution of serine by proline at amino acid 642 (p.Ser642Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.005308 (188/35420 alleles) in Latio/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.724, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). This variant has been detected in at least one individual with Pendred syndrome who was reported to have a second pathogenic SLC26A4 variant with an unknown phase (0.5 PM3 points, SCV000060117.6.6) (PM3_Supporting). At least one proband with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PP4, SCV000060117.6.6). In summary, due to conflicting evidence, this variant has been classified as uncertain for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: BS1, PP3, PM3_Supporting, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132685/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4 B:4
• Conservation: PhyloP100: 2.53
• Publications: 0 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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: Uncertain_significance. The variant received -1 ACMG points.

• PM3: 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.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1924T>C	p.Ser642Pro	missense	Exon 17 of 21	NP_000432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1924T>C	p.Ser642Pro	missense	Exon 17 of 21	ENSP00000494017.1
	SLC26A4	ENST00000492030.2	TSL:5	n.211T>C		non_coding_transcript_exon	Exon 2 of 6
	SLC26A4	ENST00000644846.1		n.634T>C		non_coding_transcript_exon	Exon 7 of 10	ENSP00000494344.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000740 AC: 186 AN: 251202 AF XY: 0.000530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1461094 Hom.: 0 Cov.: 31 AF XY: 0.000122 AC XY: 89 AN XY: 726910

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00487 AC: 218 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86240

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111308

Other (OTH) AF: 0.0000663 AC: 4 AN: 60356

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74498

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.00274 AC: 42 AN: 15302

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000104 Hom.: 0

Bravo AF: 0.000442

ExAC AF: 0.000552 AC: 67

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	not specified (2)
-	2	-	Pendred syndrome (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	Pathogenic	0.65
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.018	T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.72
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.45		Gain of loop (P = 0.1069)
MVP		0.97
MPC		0.068
ClinPred		0.10	T
GERP RS		4.7
Varity_R		0.63
gMVP		0.73
Mutation Taster		=18/82	disease causing

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: rs397516423; hg19: chr7-107342392;