chr4-138183287-G-T

Variant names:

• chr4-138183287-G-T
• rs1736792173
• NM_014331.4:c.934C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014331.4(SLC7A11):​c.934C>A​(p.Leu312Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. L312V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC7A11 NM_014331.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28291202).

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.934C>A	p.Leu312Met	missense	Exon 8 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.934C>A	p.Leu312Met	missense	Exon 8 of 12	ENSP00000280612.5	Q9UPY5
	SLC7A11	ENST00000509248.1	TSL:5	n.210C>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000424046.1	H0Y9F9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.065
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.22
Sift	Benign	0.086	T
Sift4G	Benign	0.11	T
Polyphen		0.11	B
Vest4		0.32
MutPred		0.59		Loss of catalytic residue at L312 (P = 0.0729)
MVP		0.54
MPC		0.32
ClinPred		0.50	T
GERP RS		3.5
Varity_R		0.18
gMVP		0.39
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1736792173; hg19: chr4-139104441;