Genetic Variant NM_000441.2:c.2T>A (chr7-107661643-T-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000441.2(SLC26A4):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

1 publications found

Variant links:

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 links:

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

SLC26A4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 107661702. Lost 0.026 part of the original CDS.

PS1

Another start lost variant in NM_000441.2 (SLC26A4) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

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.2T>A	p.Met1?	start_lost	Exon 2 of 21	NP_000432.1	O43511-1
	SLC26A4-AS1	NR_028137.1		n.156A>T		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC26A4	ENST00000644269.2	MANE Select	c.2T>A	p.Met1?	start_lost	Exon 2 of 21	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000888701.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 20	ENSP00000558760.1
SLC26A4	ENST00000888700.1		c.2T>A	p.Met1?	start_lost	Exon 2 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32658

American (AMR)

AF:

0.00

AC:

AN:

38430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25416

East Asian (EAS)

AF:

0.00

AC:

AN:

37702

South Asian (SAS)

AF:

0.00

AC:

AN:

80854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091652

Other (OTH)

AF:

0.0000170

AC:

AN:

58824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.15

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.12

PhyloP100

2.9

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.61

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

0.020

Vest4

0.92

MutPred

0.99

Gain of ubiquitination at M1 (P = 0.0138)

MVP

0.92

ClinPred

0.98

GERP RS

3.8

Varity_R

0.86

gMVP

0.70

Mutation Taster

=12/188

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over