6-53499011-GTT-GTTT

Variant names:

• chr6-53499011-G-GT
• rs17880610
• NM_001498.4:c.1703-45dupA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001498.4(GCLC):​c.1703-45dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,019,698 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 30)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: GCLC NM_001498.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660
• Publications: 0 publications found

Genes affected

GCLC (HGNC:4311): (glutamate-cysteine ligase catalytic 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. This locus encodes the catalytic subunit, while the regulatory subunit is derived from a different gene located on chromosome 1p22-p21. Mutations at this locus have been associated with hemolytic anemia due to deficiency of gamma-glutamylcysteine synthetase and susceptibility to myocardial infarction.[provided by RefSeq, Oct 2010]

GCLC-AS1 (HGNC:56649): (GCLC antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.0182) population. However there is too low homozygotes in high coverage region: (expected more than 48, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001498.4. 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
	GCLC	NM_001498.4	MANE Select	c.1703-45dupA		intron	N/A	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.1589-45dupA		intron	N/A	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-7133dupT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.1703-45_1703-44insA		intron	N/A	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.1544-45_1544-44insA		intron	N/A	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000515580.1	TSL:1	n.1307-45_1307-44insA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000802 AC: 12 AN: 149624 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000987

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000744

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00649 AC: 1151 AN: 177400 AF XY: 0.00674

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00899

Gnomad EAS exome AF: 0.00373

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00638

Gnomad OTH exome AF: 0.00468

GnomAD4 exome AF: 0.0161 AC: 14039 AN: 870074 Hom.: 0 Cov.: 12 AF XY: 0.0153 AC XY: 6861 AN XY: 447222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0137 AC: 286 AN: 20852

American (AMR) AF: 0.00783 AC: 269 AN: 34356

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 214 AN: 18516

East Asian (EAS) AF: 0.0120 AC: 332 AN: 27566

South Asian (SAS) AF: 0.00668 AC: 420 AN: 62884

European-Finnish (FIN) AF: 0.0102 AC: 452 AN: 44358

Middle Eastern (MID) AF: 0.00943 AC: 41 AN: 4350

European-Non Finnish (NFE) AF: 0.0185 AC: 11461 AN: 619160

Other (OTH) AF: 0.0148 AC: 564 AN: 38032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000802 AC: 12 AN: 149624 Hom.: 0 Cov.: 30 AF XY: 0.0000823 AC XY: 6 AN XY: 72868

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000983 AC: 4 AN: 40684

American (AMR) AF: 0.0000666 AC: 1 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4716

European-Finnish (FIN) AF: 0.0000987 AC: 1 AN: 10130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000744 AC: 5 AN: 67230

Other (OTH) AF: 0.00 AC: 0 AN: 2054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000145984), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0298 Hom.: 107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.066
Mutation Taster		=100/0	polymorphism

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: rs17880610; hg19: chr6-53363809; COSMIC: COSV57597526; COSMIC: COSV57597526;