rs1135402753

chr6-31874723-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_025257.3(SLC44A4):c.466A>G(p.Met156Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC44A4 NM_025257.3 missense, splice_region
• Scores: Splicing: ADA: 0.1523
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.652

Genes affected

SLC44A4 (HGNC:13941): (solute carrier family 44 member 4) The protein encoded by this gene may be a sodium-dependent transmembrane transport protein involved in the uptake of choline by cholinergic neurons. Defects in this gene can cause sialidosis, a lysosomal storage disease. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-31874723-T-C is Pathogenic according to our data. Variant chr6-31874723-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 431429.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null. Variant chr6-31874723-T-C is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12831709).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC44A4	NM_025257.3	c.466A>G	p.Met156Val	missense_variant, splice_region_variant	6/21	ENST00000229729.11
SLC44A4	NM_001178045.2	c.238A>G	p.Met80Val	missense_variant, splice_region_variant	6/21
SLC44A4	NM_001178044.2	c.343-203A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC44A4	ENST00000229729.11	c.466A>G	p.Met156Val	missense_variant, splice_region_variant	6/21	1	NM_025257.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hearing loss, autosomal dominant 72 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	17
Dann	Benign	0.84
DEOGEN2	Benign	0.0092	T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.99	N;N;.
REVEL	Benign	0.084
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.26	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.26
MutPred		0.48		Gain of sheet (P = 0.0827);.;.;
MVP		0.29
MPC		0.23
ClinPred		0.073	T
GERP RS		2.4
Varity_R		0.16
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135402753; hg19: chr6-31842500;