chr1-93894551-C-A

Variant names:

• chr1-93894551-C-A
• rs769211
• NM_002061.4:c.655+63G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002061.4(GCLM):​c.655+63G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 885,808 control chromosomes in the GnomAD database, including 29,253 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 0.26 (5188 hom., cov: 32)
  • Exomes 𝑓: 0.25 (24065 hom.)
• Consequence: GCLM NM_002061.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0500
• Publications: 10 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]

ENSG00000310419 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLM	NM_002061.4	MANE Select	c.655+63G>T		intron	N/A	NP_002052.1	P48507-1
	GCLM	NM_001308253.2		c.589+63G>T		intron	N/A	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.655+63G>T		intron	N/A	ENSP00000359258.3	P48507-1
	GCLM	ENST00000615724.1	TSL:1	c.589+63G>T		intron	N/A	ENSP00000484507.1	P48507-2
	GCLM	ENST00000871361.1		c.709+63G>T		intron	N/A	ENSP00000541420.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39246 AN: 151878 Hom.: 5183 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.253

GnomAD4 exome AF: 0.249 AC: 182852 AN: 733812 Hom.: 24065 AF XY: 0.241 AC XY: 94184 AN XY: 390012

African (AFR) AF: 0.244 AC: 4622 AN: 18942

American (AMR) AF: 0.377 AC: 14565 AN: 38592

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 4680 AN: 20350

East Asian (EAS) AF: 0.154 AC: 5550 AN: 35956

South Asian (SAS) AF: 0.117 AC: 7946 AN: 67912

European-Finnish (FIN) AF: 0.239 AC: 12028 AN: 50414

Middle Eastern (MID) AF: 0.194 AC: 781 AN: 4034

European-Non Finnish (NFE) AF: 0.268 AC: 123843 AN: 461678

Other (OTH) AF: 0.246 AC: 8837 AN: 35934

GnomAD4 genome AF: 0.258 AC: 39268 AN: 151996 Hom.: 5188 Cov.: 32 AF XY: 0.258 AC XY: 19198 AN XY: 74276

African (AFR) AF: 0.250 AC: 10368 AN: 41452

American (AMR) AF: 0.348 AC: 5312 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 788 AN: 3470

East Asian (EAS) AF: 0.165 AC: 851 AN: 5172

South Asian (SAS) AF: 0.115 AC: 556 AN: 4830

European-Finnish (FIN) AF: 0.239 AC: 2513 AN: 10530

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18076 AN: 67962

Other (OTH) AF: 0.251 AC: 529 AN: 2110

Alfa AF: 0.265 Hom.: 12260

Bravo AF: 0.270

Asia WGS AF: 0.144 AC: 497 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.1
DANN	Benign	0.46
PhyloP100		0.050
Mutation Taster		=99/1	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: rs769211; hg19: chr1-94360107;