rs145805875

chr7-107710095-G-Achr7-107710095-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000441.2(SLC26A4):c.2131G>A(p.Asp711Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.62

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2131G>A	p.Asp711Asn	missense_variant	19/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2131G>A	p.Asp711Asn	missense_variant	19/21		NM_000441.2	P1
SLC26A4	ENST00000644846.1	c.*33G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10
SLC26A4	ENST00000492030.2	n.377-60G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459284 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 20, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 31, 2011

The Asp711Asn variant has not been reported in the literature nor previously ide ntified by our laboratory. This residue is well conserved across mammals and mos t vertebrates; however, it is replaced with glutamic acid in zebrafish. Computat ional analyses (amino acid properties, PolyPhen2, SIFT, AlignGVGD) provide incon sistent predictions on the impact of the variant. It should be noted that this l ab has only sequenced SLC26A4 in 44 Asian probands and no Asian healthy controls . In addition, healthy control information is limited in either public databases or scientific literature, such that the full spectrum of benign variation has n ot yet been defined for this population. Future analysis could reveal that the A sp711Asn variant is common in this population and therefore unlikely to be patho genic. In summary, the clinical significance of this variant is not clear at thi s time. -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.52
Sift	Benign	0.48	T;.
Sift4G	Benign	0.078	T;.
Polyphen		1.0	D;D
Vest4		0.59
MutPred		0.43		Loss of ubiquitination at K715 (P = 0.1647);Loss of ubiquitination at K715 (P = 0.1647);
MVP		0.99
MPC		0.072
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145805875; hg19: chr7-107350540; COSMIC: COSV55917059;