chr22-21029213-C-G

Variant names:

• chr22-21029213-C-G
• rs1211587445
• NM_004173.3:c.1750G>C

Variant summary

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

The NM_004173.3(SLC7A4):​c.1750G>C​(p.Gly584Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,502 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G584S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC7A4 NM_004173.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48

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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A4	NM_004173.3	c.1750G>C	p.Gly584Arg	missense_variant	Exon 5 of 5	ENST00000382932.3	NP_004164.2
SLC7A4	XM_047441472.1	c.1750G>C	p.Gly584Arg	missense_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.1750G>C	p.Gly584Arg	missense_variant	Exon 5 of 5	1	NM_004173.3	ENSP00000372390.2
SLC7A4	ENST00000403586.5	c.1750G>C	p.Gly584Arg	missense_variant	Exon 5 of 5	1		ENSP00000384278.1
ENSG00000291240	ENST00000706202.1	n.1732+123G>C		intron_variant	Intron 4 of 6			ENSP00000516280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000313 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.9	H;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.099	T;T
Sift4G	Benign	0.31	T;T
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.84		Gain of methylation at G584 (P = 0.0072);Gain of methylation at G584 (P = 0.0072);
MVP		0.91
MPC		0.42
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.22
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1211587445; hg19: chr22-21383502;