rs7515191

Positions:

• chr1-93901541-G-A

Variant summary

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

The NM_002061.4(GCLM):​c.277+44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 975,892 control chromosomes in the GnomAD database, including 69,074 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 0.44 (16906 hom., cov: 32)
  • Exomes 𝑓: 0.35 (52168 hom.)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCLM	NM_002061.4	c.277+44C>T		intron_variant		ENST00000370238.8
GCLM	NM_001308253.2	c.211+44C>T		intron_variant
GCLM	XM_011541261.3	c.13+44C>T		intron_variant
GCLM	XM_047418031.1	c.277+44C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCLM	ENST00000370238.8	c.277+44C>T		intron_variant		1	NM_002061.4	P1
GCLM	ENST00000615724.1	c.211+44C>T		intron_variant		1
GCLM	ENST00000467772.1	n.277+44C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67509 AN: 151840 Hom.: 16871 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.362 AC: 82965 AN: 229424 Hom.: 16583 AF XY: 0.348 AC XY: 43332 AN XY: 124528

Gnomad AFR exome AF: 0.690

Gnomad AMR exome AF: 0.477

Gnomad ASJ exome AF: 0.312

Gnomad EAS exome AF: 0.207

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.349

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.346 AC: 284685 AN: 823934 Hom.: 52168 Cov.: 11 AF XY: 0.339 AC XY: 147705 AN XY: 435296

Gnomad4 AFR exome AF: 0.691

Gnomad4 AMR exome AF: 0.472

Gnomad4 ASJ exome AF: 0.318

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.350

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.445 AC: 67600 AN: 151958 Hom.: 16906 Cov.: 32 AF XY: 0.442 AC XY: 32844 AN XY: 74284

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.416

Alfa AF: 0.371 Hom.: 10962

Bravo AF: 0.467

Asia WGS AF: 0.247 AC: 858 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.75
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7515191; hg19: chr1-94367097; COSMIC: COSV64687734; COSMIC: COSV64687734;