6-31863662-C-G

Position:

• chr6-31863662-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025257.3(SLC44A4):​c.2098G>C​(p.Glu700Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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: -0.733

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048222184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A4	NM_025257.3	c.2098G>C	p.Glu700Gln	missense_variant	21/21	ENST00000229729.11	NP_079533.2
SLC44A4	NM_001178044.2	c.1972G>C	p.Glu658Gln	missense_variant	20/20		NP_001171515.1
SLC44A4	NM_001178045.2	c.1870G>C	p.Glu624Gln	missense_variant	21/21		NP_001171516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A4	ENST00000229729.11	c.2098G>C	p.Glu700Gln	missense_variant	21/21	1	NM_025257.3	ENSP00000229729	P1
SLC44A4	ENST00000375562.8	c.1972G>C	p.Glu658Gln	missense_variant	20/20	2		ENSP00000364712
SLC44A4	ENST00000544672.5	c.1870G>C	p.Glu624Gln	missense_variant	21/21	2		ENSP00000444109
SLC44A4	ENST00000487680.1	n.307G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with SLC44A4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 700 of the SLC44A4 protein (p.Glu700Gln). 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	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Benign	0.78
DEOGEN2	Benign	0.0038	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.055	N
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.64	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.080	N;N;N;.
REVEL	Benign	0.048
Sift	Benign	0.35	T;T;T;.
Sift4G	Benign	0.33	T;T;T;.
Polyphen		0.013	B;.;.;.
Vest4		0.032
MutPred		0.30		Gain of MoRF binding (P = 0.0186);.;.;.;
MVP		0.030
MPC		0.21
ClinPred		0.10	T
GERP RS		-4.4
Varity_R		0.11
gMVP		0.46

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: rs1762676479; hg19: chr6-31831439;