rs12140446

chr1-93899003-T-Achr1-93899003-T-Cchr1-93899003-T-G

Variant summary

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

The NM_002061.4(GCLM):c.278-1105A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,048 control chromosomes in the GnomAD database, including 7,266 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 0.28 (7266 hom., cov: 31)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458

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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLM	NM_002061.4	c.278-1105A>T		intron_variant		ENST00000370238.8
GCLM	NM_001308253.2	c.212-1105A>T		intron_variant
GCLM	XM_011541261.3	c.14-1105A>T		intron_variant
GCLM	XM_047418031.1	c.278-1105A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLM	ENST00000370238.8	c.278-1105A>T		intron_variant		1	NM_002061.4	P1
GCLM	ENST00000615724.1	c.212-1105A>T		intron_variant		1
GCLM	ENST00000467772.1	n.278-1105A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43284 AN: 151930 Hom.: 7270 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.319

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

GnomAD4 genome AF: 0.285 AC: 43276 AN: 152048 Hom.: 7266 Cov.: 31 AF XY: 0.287 AC XY: 21353 AN XY: 74318

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.537

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.283

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.317

Alfa AF: 0.302 Hom.: 920

Bravo AF: 0.280

Asia WGS AF: 0.484 AC: 1681 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	13
Dann	Benign	0.88

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: rs12140446; hg19: chr1-94364559;