1-93907322-T-C

Position:

• chr1-93907322-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002061.4(GCLM):​c.126+1716A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 152,108 control chromosomes in the GnomAD database, including 29,803 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.62 (29803 hom., cov: 32)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCLM	NM_002061.4	c.126+1716A>G		intron_variant		ENST00000370238.8	NP_002052.1
GCLM	NM_001308253.2	c.126+1716A>G		intron_variant			NP_001295182.1
GCLM	XM_047418031.1	c.126+1716A>G		intron_variant			XP_047273987.1
GCLM	XM_011541261.3	c.-139+1343A>G		intron_variant			XP_011539563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCLM	ENST00000370238.8	c.126+1716A>G		intron_variant		1	NM_002061.4	ENSP00000359258.3
GCLM	ENST00000615724.1	c.126+1716A>G		intron_variant		1		ENSP00000484507.1
GCLM	ENST00000462183.1	n.260+1343A>G		intron_variant		3
GCLM	ENST00000467772.1	n.126+1343A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93917 AN: 151990 Hom.: 29794 Cov.: 32

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.643

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.618 AC: 93955 AN: 152108 Hom.: 29803 Cov.: 32 AF XY: 0.618 AC XY: 45929 AN XY: 74354

Gnomad4 AFR AF: 0.458

Gnomad4 AMR AF: 0.674

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.767

Gnomad4 SAS AF: 0.669

Gnomad4 FIN AF: 0.635

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.639

Alfa AF: 0.675 Hom.: 45487

Bravo AF: 0.613

Asia WGS AF: 0.688 AC: 2391 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.6
DANN	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs2301022; hg19: chr1-94372878;