chr6-53497649-GA-G

Variant names:

• chr6-53497647-GA-GAG
• rs1225357173
• NM_001498.4:c.*1107dupC

Variant summary

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

The NM_001498.4(GCLC):​c.*1107dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000792 in 126,320 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 0.0000079 (0 hom., cov: 31)
• Consequence: GCLC NM_001498.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• 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: Very rare variant in population databases, with high coverage

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.*1107dupC		3_prime_UTR	Exon 16 of 16	NP_001489.1	P48506
	GCLC	NM_001197115.2		c.*1107dupC		3_prime_UTR	Exon 15 of 15	NP_001184044.1	E1CEI4
	GCLC-AS1	NR_183318.1		n.327-8505dupG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCLC	ENST00000650454.1	MANE Select	c.*1107dupC		3_prime_UTR	Exon 16 of 16	ENSP00000497574.1	P48506
	GCLC	ENST00000616923.5	TSL:1	c.*1107dupC		3_prime_UTR	Exon 16 of 16	ENSP00000482756.2	B4E2I4
	GCLC	ENST00000509541.5	TSL:5	c.*1107dupC		3_prime_UTR	Exon 10 of 10	ENSP00000495056.1	A0A2R8Y648

Frequencies

GnomAD3 genomes AF: 0.00000792 AC: 1 AN: 126320 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000165

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00000792 AC: 1 AN: 126320 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 61566

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

African (AFR) AF: 0.00 AC: 0 AN: 30922

American (AMR) AF: 0.00 AC: 0 AN: 11100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3150

East Asian (EAS) AF: 0.00 AC: 0 AN: 4328

South Asian (SAS) AF: 0.00 AC: 0 AN: 4118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000165 AC: 1 AN: 60556

Other (OTH) AF: 0.00 AC: 0 AN: 1804

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1225357173; hg19: chr6-53362445;