chr1-93907322-T-C

Variant names:

• chr1-93907322-T-C
• rs2301022
• NM_002061.4:c.126+1716A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 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: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLM	NM_002061.4	MANE Select	c.126+1716A>G		intron	N/A	NP_002052.1
	GCLM	NM_001308253.2		c.126+1716A>G		intron	N/A	NP_001295182.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLM	ENST00000370238.8	TSL:1 MANE Select	c.126+1716A>G		intron	N/A	ENSP00000359258.3
	GCLM	ENST00000615724.1	TSL:1	c.126+1716A>G		intron	N/A	ENSP00000484507.1
	GCLM	ENST00000871361.1		c.126+1716A>G		intron	N/A	ENSP00000541420.1

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

African (AFR) AF: 0.458 AC: 19010 AN: 41488

American (AMR) AF: 0.674 AC: 10298 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2271 AN: 3472

East Asian (EAS) AF: 0.767 AC: 3969 AN: 5174

South Asian (SAS) AF: 0.669 AC: 3222 AN: 4814

European-Finnish (FIN) AF: 0.635 AC: 6704 AN: 10562

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46299 AN: 67998

Other (OTH) AF: 0.639 AC: 1349 AN: 2112

Alfa AF: 0.668 Hom.: 56636

Bravo AF: 0.613

Asia WGS AF: 0.688 AC: 2391 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.6
DANN	Benign	0.74
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

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: rs2301022; hg19: chr1-94372878;