7-107689054-T-C

Variant names:

• chr7-107689054-T-C
• rs111033212
• NM_000441.2:c.1003T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 5 ACMG points: 6P and 1B. BS1_Supporting PS3_Supporting PP3 PP1 PP4 PM3

This summary comes from the ClinGen Evidence Repository: The c.1003T>C (p.Phe335Leu) variant has been identified in over 20 probands with Hearing loss, 6 of whom had a second pathogenic or suspected pathogenic variant in trans (PM3_VeryStrong; PMIDs: 19509082, 29293505, 25394566, 20668687, 20597900, 19426954, 19204907, 18285825, 17503324, 17357124, 17309986, 15689455, 14679580, 11317356, Laboratory for Molecular Medicine internal data). The variant has been reported to segregate with disease in one affected family member (PP1; PMID:18285825). Multiple probands presented with hearing loss and enlarged vestibular aqueducts (EVA) which are highly specific to Pendred syndrome (PP4; PMIDs: 14679580, 18285825, 19509082, 25394566, Laboratory for Molecular Medicine internal data). Evidence has been published indicating that the p.Phe335Leu variant may be pathogenic when in trans with a functionally-null or severely hypomorphic variant but not as a mono-allelic variant or in the homozygous state (PMIDs: 19204907, 24051746). The c.1003T>C (p.Phe335Leu) variant was present in 0.203% (76/30612 CI 95%) of South Asian alleles in gnomAD v2.1.1, which is a high enough frequency apply BS1_Supporting. Additionally it was present in 2.1% (27/910 CI 95%) of Amish alleles in gnomAD v3.1 (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for Pendred syndrome outweighs the high allele frequency of the variant in population databases. Therefore, neither BS1_Supporting nor BA1 will contribute to the overall classification. A functional study demonstrates that the p.Phe335Leu variant may impact protein function (PS3_Supporting; PMID:19204907). Finally, the REVEL computational prediction analysis tool produced a score of 0.828, which is above the threshold necessary to apply PP3. In summary, this variant has been classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PS3_Supporting, PP1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253316/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.5408
• Clinical Significance: Likely pathogenic reviewed by expert panel P:23 U:3
• Conservation: PhyloP100: 6.64
• Publications: 38 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_pathogenic. The variant received 5 ACMG points.

• PS3: 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.
• 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.1003T>C	p.Phe335Leu	missense splice_region	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.1003T>C	p.Phe335Leu	missense splice_region	Exon 9 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1003T>C	p.Phe335Leu	missense splice_region	Exon 8 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1003T>C	p.Phe335Leu	missense splice_region	Exon 9 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000860 AC: 216 AN: 251190 AF XY: 0.000935

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00136 AC: 1981 AN: 1461496 Hom.: 5 Cov.: 31 AF XY: 0.00143 AC XY: 1038 AN XY: 727058

African (AFR) AF: 0.000149 AC: 5 AN: 33452

American (AMR) AF: 0.0000447 AC: 2 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00248 AC: 214 AN: 86256

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00148 AC: 1641 AN: 1111732

Other (OTH) AF: 0.00133 AC: 80 AN: 60372

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74442

African (AFR) AF: 0.0000963 AC: 4 AN: 41556

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68010

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000993 Hom.: 1

Bravo AF: 0.000910

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	1	-	Autosomal recessive nonsyndromic hearing loss 4 (7)
5	2	-	not provided (7)
7	-	-	Pendred syndrome (7)
2	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)
2	-	-	SLC26A4-related disorder (2)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.85	L
PhyloP100		6.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Benign	0.73	T
Sift4G	Benign	0.74	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.88		Gain of disorder (P = 0.1119)
MVP		0.97
MPC		0.076
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.65
gMVP		0.89
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.15		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: rs111033212; hg19: chr7-107329499;