4-138180715-G-C

Variant names:

• chr4-138180715-G-C
• rs201882877
• NM_014331.4:c.1192C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014331.4(SLC7A11):​c.1192C>G​(p.Leu398Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. L398F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SLC7A11 NM_014331.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014331.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A11	NM_014331.4	MANE Select	c.1192C>G	p.Leu398Val	missense	Exon 10 of 12	NP_055146.1	Q9UPY5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A11	ENST00000280612.9	TSL:1 MANE Select	c.1192C>G	p.Leu398Val	missense	Exon 10 of 12	ENSP00000280612.5	Q9UPY5
	SLC7A11	ENST00000509248.1	TSL:5	n.*143C>G		non_coding_transcript_exon	Exon 5 of 7	ENSP00000424046.1	H0Y9F9
	SLC7A11	ENST00000509248.1	TSL:5	n.*143C>G		3_prime_UTR	Exon 5 of 7	ENSP00000424046.1	H0Y9F9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250176 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.038
Eigen_PC	Benign	0.073
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.027	D
Polyphen		0.060	B
Vest4		0.54
MVP		0.75
MPC		0.52
ClinPred		0.89	D
GERP RS		3.1
Varity_R		0.63
gMVP		0.74
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.79		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201882877; hg19: chr4-139101869;