Variant chr6-31863743-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_025257.3(SLC44A4):c.2017G>C(p.Asp673His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC44A4
NM_025257.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.44

Variant links:

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]

SLC44A4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3 link	c.2017G>C	p.Asp673His	missense_variant	21/21	ENST00000229729.11	NP_079533.2	Q53GD3-1A0A140VJH4
SLC44A4	NM_001178044.2 link	c.1891G>C	p.Asp631His	missense_variant	20/20		NP_001171515.1	Q53GD3-4
SLC44A4	NM_001178045.2 link	c.1789G>C	p.Asp597His	missense_variant	21/21		NP_001171516.1	Q53GD3-3A0A1U9X8K7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC44A4	ENST00000229729.11 link	c.2017G>C	p.Asp673His	missense_variant	21/21	1	NM_025257.3	ENSP00000229729.6	Q53GD3-1
SLC44A4	ENST00000375562.8 link	c.1891G>C	p.Asp631His	missense_variant	20/20	2		ENSP00000364712.4	Q53GD3-4
SLC44A4	ENST00000544672.5 link	c.1789G>C	p.Asp597His	missense_variant	21/21	2		ENSP00000444109.1	Q53GD3-3
SLC44A4	ENST00000487680.1 link	n.226G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460502

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2024

The c.2017G>C (p.D673H) alteration is located in exon 21 (coding exon 21) of the SLC44A4 gene. This alteration results from a G to C substitution at nucleotide position 2017, causing the aspartic acid (D) at amino acid position 673 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.9

H;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.5

D;D;D;.

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.93

MutPred

0.88

Gain of helix (P = 0.132);.;.;.;

MVP

0.26

MPC

0.89

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.93

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over