6-31863656-G-A

Position:

chr6-31863656-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025257.3(SLC44A4):c.2104C>T(p.Pro702Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC44A4
NM_025257.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.456

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09041053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SLC44A4	NM_025257.3 linkuse as main transcript	c.2104C>T	p.Pro702Ser	missense_variant	21/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2 linkuse as main transcript	c.1978C>T	p.Pro660Ser	missense_variant	20/20		NP_001171515.1
SLC44A4	NM_001178045.2 linkuse as main transcript	c.1876C>T	p.Pro626Ser	missense_variant	21/21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11 linkuse as main transcript	c.2104C>T	p.Pro702Ser	missense_variant	21/21	1	NM_025257.3	ENSP00000229729	P1	Q53GD3-1
SLC44A4	ENST00000375562.8 linkuse as main transcript	c.1978C>T	p.Pro660Ser	missense_variant	20/20	2		ENSP00000364712		Q53GD3-4
SLC44A4	ENST00000544672.5 linkuse as main transcript	c.1876C>T	p.Pro626Ser	missense_variant	21/21	2		ENSP00000444109		Q53GD3-3
SLC44A4	ENST00000487680.1 linkuse as main transcript	n.313C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00000408

AC:

AN:

244838

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133630

show subpopulations

Gnomad AFR exome

AF:

0.0000664

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460004

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726322

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000151

ExAC

AF:

0.00000846

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 702 of the SLC44A4 protein (p.Pro702Ser). This variant is present in population databases (rs748155512, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SLC44A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1918261). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0096

T;.;.;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.042

M_CAP

Benign

0.0056

MetaRNN

Benign

0.090

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

M;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N;N;.

REVEL

Benign

0.0030

Sift

Benign

0.082

T;T;T;.

Sift4G

Benign

0.27

T;T;T;.

Polyphen

0.035

B;.;.;.

Vest4

0.15

MutPred

0.38

Gain of phosphorylation at P702 (P = 0.0124);.;.;.;

MVP

0.014

MPC

0.22

ClinPred

0.078

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.35

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over