rs1265972101

Variant names:

• chr1-93909051-G-A
• rs1265972101
• NM_002061.4:c.113C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-93909051-G-A
• chr1-93909051-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002061.4(GCLM):​c.113C>T​(p.Thr38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,320,740 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GCLM NM_002061.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24872026).

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.113C>T	p.Thr38Met	missense	Exon 1 of 7	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.113C>T	p.Thr38Met	missense	Exon 1 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.113C>T	p.Thr38Met	missense	Exon 1 of 7	ENSP00000359258.3	P48507-1
	GCLM	ENST00000615724.1	TSL:1	c.113C>T	p.Thr38Met	missense	Exon 1 of 6	ENSP00000484507.1	P48507-2
	GCLM	ENST00000871361.1		c.113C>T	p.Thr38Met	missense	Exon 1 of 8	ENSP00000541420.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1320740 Hom.: 0 Cov.: 32 AF XY: 0.00000307 AC XY: 2 AN XY: 651666

African (AFR) AF: 0.00 AC: 0 AN: 26746

American (AMR) AF: 0.00 AC: 0 AN: 26876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23268

East Asian (EAS) AF: 0.00 AC: 0 AN: 28010

South Asian (SAS) AF: 0.00 AC: 0 AN: 73288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3942

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1049692

Other (OTH) AF: 0.00 AC: 0 AN: 54674

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.015	D
Polyphen		0.92	P
Vest4		0.22
MutPred		0.20		Gain of catalytic residue at T38 (P = 0.0266)
MVP		0.48
MPC		2.6
ClinPred		0.88	D
GERP RS		2.2
PromoterAI		-0.0062	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.24
gMVP		0.39
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs1265972101; hg19: chr1-94374607; COSMIC: COSV64687747; COSMIC: COSV64687747;