Genetic Variant SLC7A11:p.Ile378Thr (chr4-138180774-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014331.4(SLC7A11):c.1133T>C(p.Ile378Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000535 in 1,612,614 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: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

SLC7A11
NM_014331.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.12

Variant links:

Genes affected

SLC7A11 (HGNC:11059): (solute carrier family 7 member 11) This gene encodes a member of a heteromeric, sodium-independent, anionic amino acid transport system that is highly specific for cysteine and glutamate. In this system, designated Xc(-), the anionic form of cysteine is transported in exchange for glutamate. This protein has been identified as the predominant mediator of Kaposi sarcoma-associated herpesvirus fusion and entry permissiveness into cells. Also, increased expression of this gene in primary gliomas (compared to normal brain tissue) was associated with increased glutamate secretion via the XCT channels, resulting in neuronal cell death. [provided by RefSeq, Sep 2011]

SLC7A11 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13820198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A11	NM_014331.4 link	c.1133T>C	p.Ile378Thr	missense_variant	Exon 10 of 12	ENST00000280612.9	NP_055146.1	Q9UPY5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC7A11	ENST00000280612.9 link	c.1133T>C	p.Ile378Thr	missense_variant	Exon 10 of 12	1	NM_014331.4	ENSP00000280612.5	Q9UPY5
SLC7A11	ENST00000509248.1 link	n.*84T>C		non_coding_transcript_exon_variant	Exon 5 of 7	5		ENSP00000424046.1	H0Y9F9
SLC7A11	ENST00000509248.1 link	n.*84T>C		3_prime_UTR_variant	Exon 5 of 7	5		ENSP00000424046.1	H0Y9F9

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000498

AC:

124

AN:

249222

Hom.:

AF XY:

0.000490

AC XY:

AN XY:

134698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000788

Gnomad ASJ exome

AF:

0.00230

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000605

Gnomad OTH exome

AF:

0.000990

GnomAD4 exome

AF:

0.000535

AC:

782

AN:

1460328

Hom.:

Cov.:

AF XY:

0.000533

AC XY:

387

AN XY:

726434

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000651

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000611

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000532

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000726

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000453

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1133T>C (p.I378T) alteration is located in exon 10 (coding exon 10) of the SLC7A11 gene. This alteration results from a T to C substitution at nucleotide position 1133, causing the isoleucine (I) at amino acid position 378 to be replaced by a threonine (T). 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

0.26

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.80

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

M_CAP

Benign

0.061

MetaRNN

Benign

0.14

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.58

Sift

Uncertain

0.012

Sift4G

Benign

0.089

Polyphen

0.14

Vest4

0.63

MVP

0.67

MPC

0.48

ClinPred

0.065

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.56

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