Genetic Variant SLC7A4:p.Gln443Arg (chr22-21030006-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004173.3(SLC7A4):c.1328A>G(p.Gln443Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000768 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

SLC7A4
NM_004173.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.20

Variant links:

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]

SLC7A4 links:

ENSG00000291240 (HGNC:):

ENSG00000291240 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031001806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A4	NM_004173.3 link	c.1328A>G	p.Gln443Arg	missense_variant	Exon 3 of 5	ENST00000382932.3	NP_004164.2	O43246
SLC7A4	XM_047441472.1 link	c.1328A>G	p.Gln443Arg	missense_variant	Exon 2 of 4		XP_047297428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC7A4	ENST00000382932.3 link	c.1328A>G	p.Gln443Arg	missense_variant	Exon 3 of 5	1	NM_004173.3	ENSP00000372390.2	O43246
SLC7A4	ENST00000403586.5 link	c.1328A>G	p.Gln443Arg	missense_variant	Exon 3 of 5	1		ENSP00000384278.1	O43246
ENSG00000291240	ENST00000706202.1 link	n.1328A>G		non_coding_transcript_exon_variant	Exon 3 of 7			ENSP00000516280.1	A0A994J565

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000104

AC:

AN:

249494

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135248

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461520

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000388

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000354

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1328A>G (p.Q443R) alteration is located in exon 3 (coding exon 2) of the SLC7A4 gene. This alteration results from a A to G substitution at nucleotide position 1328, causing the glutamine (Q) at amino acid position 443 to be replaced by an arginine (R). 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

0.099

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.051

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.43

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0010

B;B

Vest4

0.45

MVP

0.85

MPC

0.074

ClinPred

0.073

GERP RS

5.4

Varity_R

0.15

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over