1-94837747-A-C

Position:

• chr1-94837747-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001114106.3(SLC44A3):​c.546A>C​(p.Gln182His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC44A3 NM_001114106.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.469

Genes affected

SLC44A3 (HGNC:28689): (solute carrier family 44 member 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in transmembrane transport. Predicted to be located in plasma membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC44A3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.351989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A3	NM_001114106.3	c.546A>C	p.Gln182His	missense_variant	6/15	ENST00000271227.11	NP_001107578.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A3	ENST00000271227.11	c.546A>C	p.Gln182His	missense_variant	6/15	1	NM_001114106.3	ENSP00000271227.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447398 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 29, 2024

The c.546A>C (p.Q182H) alteration is located in exon 6 (coding exon 6) of the SLC44A3 gene. This alteration results from a A to C substitution at nucleotide position 546, causing the glutamine (Q) at amino acid position 182 to be replaced by a histidine (H). 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	0.27
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	.;T;.;.;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T;T;T;T;T;D;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	.;M;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Benign	0.11	T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;D;T
Polyphen		0.84	P;P;.;.;.;.;P
Vest4		0.64
MutPred		0.22		.;Gain of catalytic residue at Q182 (P = 0.1133);.;.;.;.;.;
MVP		0.79
MPC		0.57
ClinPred		0.98	D
GERP RS		-2.2
Varity_R		0.17
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1188066622; hg19: chr1-95303303;