rs1554352240

Positions:

• chr7-107661728-G-C
• chr7-107661728-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP5_Moderate

The NM_000441.2(SLC26A4):​c.87G>C​(p.Glu29Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E29G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.78

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_000441.2 (SLC26A4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 554998
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107661726-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-107661728-G-C is Pathogenic according to our data. Variant chr7-107661728-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1065202.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.87G>C	p.Glu29Asp	missense_variant	2/21	ENST00000644269.2
SLC26A4-AS1	NR_028137.1	n.71C>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.87G>C	p.Glu29Asp	missense_variant	2/21		NM_000441.2	P1
SLC26A4-AS1	ENST00000668981.1	n.131C>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Precision Medicine Center, Zhengzhou University

-

PM2: not found in gnomAD PM3: Pathogenic mutation confirmed in trans in one patient PM5: Another pathogenic missense variant(c.85G>C, p.Glu29Gln) at the same codon PP4: Patient phenotype highly specific for gene -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.54	.;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	0.67	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.10	T;.;T
Sift4G	Benign	0.068	T;.;T
Polyphen		0.026	B;B;.
Vest4		0.76
MutPred		0.75		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.91
MPC		0.012
ClinPred		0.53	D
GERP RS		2.3
Varity_R		0.16
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-107302173;