17-1575654-T-C

Variant names:

• chr17-1575654-T-C
• rs2075913768
• NM_152346.3:c.1660A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152346.3(SLC43A2):​c.1660A>G​(p.Lys554Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000226 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SLC43A2 NM_152346.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

Genes affected

SLC43A2 (HGNC:23087): (solute carrier family 43 member 2) This gene encodes a member of the L-amino acid transporter-3 or SLC43 family of transporters. The encoded protein mediates sodium-, chloride-, and pH-independent transport of L-isomers of neutral amino acids, including leucine, phenylalanine, valine and methionine. This protein may contribute to the transfer of amino acids across the placental membrane to the fetus. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC43A2	NM_152346.3	c.1660A>G	p.Lys554Glu	missense_variant	Exon 14 of 14	ENST00000301335.10	NP_689559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC43A2	ENST00000301335.10	c.1660A>G	p.Lys554Glu	missense_variant	Exon 14 of 14	1	NM_152346.3	ENSP00000301335.5
SLC43A2	ENST00000571650.5	c.1672A>G	p.Lys558Glu	missense_variant	Exon 15 of 15	1		ENSP00000461382.1
SLC43A2	ENST00000412517.3	c.1249A>G	p.Lys417Glu	missense_variant	Exon 10 of 10	2		ENSP00000408284.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1660A>G (p.K554E) alteration is located in exon 14 (coding exon 13) of the SLC43A2 gene. This alteration results from a A to G substitution at nucleotide position 1660, causing the lysine (K) at amino acid position 554 to be replaced by a glutamic acid (E). 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	Benign	0.16
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M;.;.
PhyloP100		5.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.77	N;.;N
REVEL	Benign	0.24
Sift	Benign	0.18	T;.;T
Sift4G	Benign	0.26	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.57
MutPred		0.27		Loss of ubiquitination at K554 (P = 0.0039);.;.;
MVP		0.50
MPC		1.4
ClinPred		0.93	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.67
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs2075913768; hg19: chr17-1478948;