7-107683232-G-T

Variant names:

• chr7-107683232-G-T
• rs138462416
• NM_000441.2:c.796G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000441.2(SLC26A4):​c.796G>T​(p.Asp266Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.520
• Publications: 7 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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25447273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.796G>T	p.Asp266Tyr	missense_variant	Exon 7 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.796G>T	p.Asp266Tyr	missense_variant	Exon 7 of 21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250786 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460110 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726394

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111552

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Uncertain	0.66	D;D
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.041	N
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		-0.52
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.4	N;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		0.71	P;P
Vest4		0.39
MutPred		0.38		Gain of solvent accessibility (P = 0.1116);Gain of solvent accessibility (P = 0.1116);
MVP		0.61
MPC		0.014
ClinPred		0.34	T
GERP RS		-5.7
Varity_R		0.17
gMVP		0.81
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs138462416; hg19: chr7-107323677;