6-31864682-T-G

Variant names:

• chr6-31864682-T-G
• rs745650755
• NM_025257.3:c.1981A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025257.3(SLC44A4):​c.1981A>C​(p.Met661Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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: 6.8e-7 (0 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 661 of the SLC44A4 protein (p.Met661Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC44A4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC44A4 protein function. 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	Uncertain	0.42
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.053	T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Uncertain	0.68	T
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		0.97	D
GERP RS		3.6
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

Other links and lift over

dbSNP: rs745650755; hg19: chr6-31832459;