9-113151078-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001860.3(SLC31A2):c.4G>A(p.Ala2Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000864 in 1,156,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: SLC31A2 NM_001860.3 missense, splice_region
• Scores: Splicing: ADA: 0.0001180
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192

Genes affected

SLC31A2 (HGNC:11017): (solute carrier family 31 member 2) Predicted to enable copper ion transmembrane transporter activity. Predicted to be involved in cellular copper ion homeostasis. Predicted to act upstream of or within regulation of copper ion transmembrane transport. Predicted to be located in membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18000808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC31A2	NM_001860.3	c.4G>A	p.Ala2Thr	missense_variant, splice_region_variant	1/4	ENST00000259392.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC31A2	ENST00000259392.8	c.4G>A	p.Ala2Thr	missense_variant, splice_region_variant	1/4	1	NM_001860.3	P1
SLC31A2	ENST00000490809.1	n.103G>A		splice_region_variant, non_coding_transcript_exon_variant	1/2	2
SLC31A2	ENST00000374220.3	c.4G>A	p.Ala2Thr	missense_variant, splice_region_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.64e-7 AC: 1 AN: 1156768 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 553960

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: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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 27, 2022

The c.4G>A (p.A2T) alteration is located in exon 1 (coding exon 1) of the SLC31A2 gene. This alteration results from a G to A substitution at nucleotide position 4, causing the alanine (A) at amino acid position 2 to be replaced by a threonine (T). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.087
Sift	Benign	0.46	T
Sift4G	Benign	0.56	T
Polyphen		0.0070	B
Vest4		0.044
MutPred		0.38		Gain of glycosylation at A2 (P = 0.0105);
MVP		0.51
MPC		0.19
ClinPred		0.26	T
GERP RS		1.8
Varity_R		0.029
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0
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: rs1417875489; hg19: chr9-115913358;