Genetic Variant NM_025257.3:c.1981A>T (chr6-31864682-T-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_025257.3(SLC44A4):c.1981A>T(p.Met661Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,402 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC44A4
NM_025257.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.61

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC44A4	NM_025257.3 link	c.1981A>T	p.Met661Leu	missense_variant	Exon 20 of 21	ENST00000229729.11	NP_079533.2	Q53GD3-1A0A140VJH4
SLC44A4	NM_001178044.2 link	c.1855A>T	p.Met619Leu	missense_variant	Exon 19 of 20		NP_001171515.1	Q53GD3-4
SLC44A4	NM_001178045.2 link	c.1753A>T	p.Met585Leu	missense_variant	Exon 20 of 21		NP_001171516.1	Q53GD3-3A0A1U9X8K7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC44A4	ENST00000229729.11 link	c.1981A>T	p.Met661Leu	missense_variant	Exon 20 of 21	1	NM_025257.3	ENSP00000229729.6	Q53GD3-1
SLC44A4	ENST00000375562.8 link	c.1855A>T	p.Met619Leu	missense_variant	Exon 19 of 20	2		ENSP00000364712.4	Q53GD3-4
SLC44A4	ENST00000544672.5 link	c.1753A>T	p.Met585Leu	missense_variant	Exon 20 of 21	2		ENSP00000444109.1	Q53GD3-3
SLC44A4	ENST00000487680.1 link	n.-2A>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151520

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250944

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

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

AF:

0.00000660

AC:

AN:

151520

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73960

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.053

T;.;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Pathogenic

3.1

M;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

D;D;D;.

REVEL

Uncertain

0.44

Sift

Uncertain

0.0030

D;D;D;.

Sift4G

Uncertain

0.010

D;D;D;.

Polyphen

0.99

D;.;.;.

Vest4

0.81

MutPred

0.80

Gain of catalytic residue at M661 (P = 0.048);.;.;.;

MVP

0.16

MPC

0.78

ClinPred

0.94

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.86

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over