1-93896752-C-T

Variant names:

• chr1-93896752-C-T
• NM_002061.4:c.406G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002061.4(GCLM):​c.406G>A​(p.Val136Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,636 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. 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. V136L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GCLM NM_002061.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58

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]

ACMG classification

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=0.1317333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCLM	NM_002061.4	c.406G>A	p.Val136Ile	missense_variant	Exon 5 of 7	ENST00000370238.8	NP_002052.1
GCLM	NM_001308253.2	c.340G>A	p.Val114Ile	missense_variant	Exon 4 of 6		NP_001295182.1
GCLM	XM_047418031.1	c.406G>A	p.Val136Ile	missense_variant	Exon 5 of 7		XP_047273987.1
GCLM	XM_011541261.3	c.142G>A	p.Val48Ile	missense_variant	Exon 5 of 7		XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCLM	ENST00000370238.8	c.406G>A	p.Val136Ile	missense_variant	Exon 5 of 7	1	NM_002061.4	ENSP00000359258.3
GCLM	ENST00000615724.1	c.340G>A	p.Val114Ile	missense_variant	Exon 4 of 6	1		ENSP00000484507.1
GCLM	ENST00000467772.1	n.406G>A		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458636 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.0056
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.68	N;.
REVEL	Benign	0.11
Sift	Benign	0.20	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.0060	B;.
Vest4		0.046
MutPred		0.50		Loss of catalytic residue at V136 (P = 0.2509);.;
MVP		0.25
MPC		0.24
ClinPred		0.40	T
GERP RS		5.5
Varity_R		0.034
gMVP		0.099

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-94362308;