6-31864676-C-T

Position:

• chr6-31864676-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_025257.3(SLC44A4):​c.1987G>A​(p.Val663Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,870 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: 0.0000034 (0 hom.)
• Consequence: SLC44A4 NM_025257.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.1987G>A	p.Val663Met	missense_variant	20/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2	c.1861G>A	p.Val621Met	missense_variant	19/20		NP_001171515.1
SLC44A4	NM_001178045.2	c.1759G>A	p.Val587Met	missense_variant	20/21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.1987G>A	p.Val663Met	missense_variant	20/21	1	NM_025257.3	ENSP00000229729.6
SLC44A4	ENST00000375562.8	c.1861G>A	p.Val621Met	missense_variant	19/20	2		ENSP00000364712.4
SLC44A4	ENST00000544672.5	c.1759G>A	p.Val587Met	missense_variant	20/21	2		ENSP00000444109.1
SLC44A4	ENST00000487680.1	n.5G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D;D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.84		Loss of catalytic residue at V663 (P = 0.1334);.;.;.;
MVP		0.34
MPC		0.81
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31832453;