rs762065495

Variant names:

• chr1-93889095-G-T
• rs762065495
• NM_002061.4:c.720C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-93889095-G-T
• chr1-93889095-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002061.4(GCLM):​c.720C>A​(p.His240Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCLM NM_002061.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.94
• Publications: 2 publications found

Genes affected

GCLM (HGNC:4312): (glutamate-cysteine ligase modifier subunit) Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase, is the first rate limiting enzyme of glutathione synthesis. The enzyme consists of two subunits, a heavy catalytic subunit and a light regulatory subunit. Gamma glutamylcysteine synthetase deficiency has been implicated in some forms of hemolytic anemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

ENSG00000310419 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024723738).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002061.4. 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
	GCLM	NM_002061.4	MANE Select	c.720C>A	p.His240Gln	missense	Exon 7 of 7	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.654C>A	p.His218Gln	missense	Exon 6 of 6	NP_001295182.1	P48507-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLM	ENST00000370238.8	TSL:1 MANE Select	c.720C>A	p.His240Gln	missense	Exon 7 of 7	ENSP00000359258.3	P48507-1
	GCLM	ENST00000615724.1	TSL:1	c.654C>A	p.His218Gln	missense	Exon 6 of 6	ENSP00000484507.1	P48507-2
	GCLM	ENST00000871361.1		c.774C>A	p.His258Gln	missense	Exon 8 of 8	ENSP00000541420.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241532 AF XY: 0.00000764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449902 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721106

African (AFR) AF: 0.00 AC: 0 AN: 32840

American (AMR) AF: 0.00 AC: 0 AN: 42772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.00 AC: 0 AN: 38818

South Asian (SAS) AF: 0.00 AC: 0 AN: 84450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106144

Other (OTH) AF: 0.00 AC: 0 AN: 59914

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0010
DANN	Benign	0.83
DEOGEN2	Benign	0.22	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-3.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.020
Sift	Benign	0.64	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.44		Loss of loop (P = 0.0073)
MVP		0.21
MPC		0.30
ClinPred		0.061	T
GERP RS		-11
Varity_R		0.021
gMVP		0.34
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs762065495; hg19: chr1-94354651;