chr7-107661658-G-T

Variant names:

• chr7-107661658-G-T
• rs111033423
• NM_000441.2:c.17G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000441.2(SLC26A4):​c.17G>T​(p.Gly6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,567,808 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00086 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.233
• Publications: 9 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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• 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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0025506318).
• BP6: Variant 7-107661658-G-T is Benign according to our data. Variant chr7-107661658-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43524.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00086 (131/152386) while in subpopulation SAS AF = 0.0242 (117/4834). AF 95% confidence interval is 0.0206. There are 4 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.17G>T	p.Gly6Val	missense	Exon 2 of 21	NP_000432.1	O43511-1
	SLC26A4-AS1	NR_028137.1		n.141C>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.17G>T	p.Gly6Val	missense	Exon 2 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.17G>T	p.Gly6Val	missense	Exon 1 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.17G>T	p.Gly6Val	missense	Exon 2 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000860 AC: 131 AN: 152268 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00248 AC: 440 AN: 177348 AF XY: 0.00312

Gnomad AFR exome AF: 0.000105

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00319

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.0000768

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00113 AC: 1597 AN: 1415422 Hom.: 30 Cov.: 30 AF XY: 0.00155 AC XY: 1089 AN XY: 701032

African (AFR) AF: 0.00 AC: 0 AN: 32746

American (AMR) AF: 0.0000256 AC: 1 AN: 39014

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 66 AN: 25480

East Asian (EAS) AF: 0.00 AC: 0 AN: 37816

South Asian (SAS) AF: 0.0166 AC: 1347 AN: 81316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40158

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5574

European-Non Finnish (NFE) AF: 0.0000685 AC: 75 AN: 1094342

Other (OTH) AF: 0.00181 AC: 107 AN: 58976

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152386 Hom.: 4 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74524

African (AFR) AF: 0.0000721 AC: 3 AN: 41594

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0242 AC: 117 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000492 Hom.: 3

Bravo AF: 0.000200

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000127 AC: 1

ExAC AF: 0.00227 AC: 263

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Pendred syndrome (4)
-	-	3	not provided (3)
-	1	1	Autosomal recessive nonsyndromic hearing loss 4 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.23
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.33
Sift	Benign	0.35	T
Sift4G	Benign	0.35	T
Polyphen		0.0050	B
Vest4		0.15
MVP		0.61
MPC		0.012
ClinPred		0.0063	T
GERP RS		0.15
Varity_R		0.061
gMVP		0.42
Mutation Taster		=99/1	polymorphism

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: rs111033423; hg19: chr7-107302103;