22-21029230-C-T

Variant names:

• chr22-21029230-C-T
• NM_004173.3:c.1733G>A

Variant summary

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

The NM_004173.3(SLC7A4):​c.1733G>A​(p.Gly578Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC7A4 NM_004173.3 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

Genes affected

SLC7A4 (HGNC:11062): (solute carrier family 7 member 4) Predicted to enable amino acid transmembrane transporter activity. Predicted to be involved in amino acid transport. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000291240 (HGNC:):

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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A4	NM_004173.3	c.1733G>A	p.Gly578Glu	missense_variant, splice_region_variant	Exon 5 of 5	ENST00000382932.3	NP_004164.2
SLC7A4	XM_047441472.1	c.1733G>A	p.Gly578Glu	missense_variant, splice_region_variant	Exon 4 of 4		XP_047297428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A4	ENST00000382932.3	c.1733G>A	p.Gly578Glu	missense_variant, splice_region_variant	Exon 5 of 5	1	NM_004173.3	ENSP00000372390.2
SLC7A4	ENST00000403586.5	c.1733G>A	p.Gly578Glu	missense_variant, splice_region_variant	Exon 5 of 5	1		ENSP00000384278.1
ENSG00000291240	ENST00000706202.1	n.1732+106G>A		intron_variant	Intron 4 of 6			ENSP00000516280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1733G>A (p.G578E) alteration is located in exon 5 (coding exon 4) of the SLC7A4 gene. This alteration results from a G to A substitution at nucleotide position 1733, causing the glycine (G) at amino acid position 578 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.86		Loss of MoRF binding (P = 0.0615);Loss of MoRF binding (P = 0.0615);
MVP		0.95
MPC		0.43
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.090		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: chr22-21383519;