1-75219327-C-A

Position:

• chr1-75219327-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001130058.2(SLC44A5):​c.1196G>T​(p.Gly399Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC44A5 NM_001130058.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

Genes affected

SLC44A5 (HGNC:28524): (solute carrier family 44 member 5) 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC44A5	NM_001130058.2	c.1196G>T	p.Gly399Val	missense_variant	16/24	ENST00000370859.8	NP_001123530.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC44A5	ENST00000370859.8	c.1196G>T	p.Gly399Val	missense_variant	16/24	2	NM_001130058.2	ENSP00000359896.3
SLC44A5	ENST00000370855.5	c.1196G>T	p.Gly399Val	missense_variant	16/24	1		ENSP00000359892.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460042 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726414

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 12, 2024

The c.1196G>T (p.G399V) alteration is located in exon 16 (coding exon 15) of the SLC44A5 gene. This alteration results from a G to T substitution at nucleotide position 1196, causing the glycine (G) at amino acid position 399 to be replaced by a valine (V). 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	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.97	.;D
Vest4		0.92
MutPred		0.82		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.62
MPC		0.98
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.98

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: chr1-75685012; COSMIC: COSV100902887;