6-31864697-A-G

Position:

• chr6-31864697-A-G

Variant summary

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

The NM_025257.3(SLC44A4):​c.1966T>C​(p.Phe656Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

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, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.1966T>C	p.Phe656Leu	missense_variant	20/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2	c.1840T>C	p.Phe614Leu	missense_variant	19/20		NP_001171515.1
SLC44A4	NM_001178045.2	c.1738T>C	p.Phe580Leu	missense_variant	20/21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.1966T>C	p.Phe656Leu	missense_variant	20/21	1	NM_025257.3	ENSP00000229729.6
SLC44A4	ENST00000375562.8	c.1840T>C	p.Phe614Leu	missense_variant	19/20	2		ENSP00000364712.4
SLC44A4	ENST00000544672.5	c.1738T>C	p.Phe580Leu	missense_variant	20/21	2		ENSP00000444109.1
SLC44A4	ENST00000487680.1	n.-17T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.1966T>C (p.F656L) alteration is located in exon 20 (coding exon 20) of the SLC44A4 gene. This alteration results from a T to C substitution at nucleotide position 1966, causing the phenylalanine (F) at amino acid position 656 to be replaced by a leucine (L). 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	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.8	D;D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;.
Polyphen		0.97	D;.;.;.
Vest4		0.91
MutPred		0.75		Loss of glycosylation at S653 (P = 0.08);.;.;.;
MVP		0.21
MPC		0.88
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.64
gMVP		0.85

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: rs1762744061; hg19: chr6-31832474;