6-53564474-A-G

Variant names:

• chr6-53564474-A-G
• rs1883633
• ENST00000505995.5:n.376-54T>C

Variant summary

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

The ENST00000505197.1(GCLC):​c.-313-54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,206 control chromosomes in the GnomAD database, including 1,697 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 0.15 (1695 hom., cov: 32)
  • Exomes 𝑓: 0.32 (2 hom.)
• Consequence: GCLC ENST00000505197.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.337
• Publications: 7 publications found

Genes affected

KILH (HGNC:56729): (KRT19 interacting long noncoding RNA in hepatocellular carcinoma)

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 Gene-Disease associations (from GenCC):

• gamma-glutamylcysteine synthetase deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000505197.1. 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
	KILH	NR_110840.1		n.400-54T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KILH	ENST00000505995.5	TSL:1	n.376-54T>C		intron	N/A
	GCLC	ENST00000505197.1	TSL:4	c.-313-54T>C		intron	N/A	ENSP00000427403.1	D6RIT4
	KILH	ENST00000502390.5	TSL:2	n.522-54T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22195 AN: 152066 Hom.: 1694 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.318 AC: 7 AN: 22 Hom.: 2 AF XY: 0.286 AC XY: 4 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.318 AC: 7 AN: 22

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.146 AC: 22207 AN: 152184 Hom.: 1695 Cov.: 32 AF XY: 0.149 AC XY: 11081 AN XY: 74402

African (AFR) AF: 0.136 AC: 5665 AN: 41522

American (AMR) AF: 0.109 AC: 1669 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 628 AN: 3472

East Asian (EAS) AF: 0.262 AC: 1358 AN: 5174

South Asian (SAS) AF: 0.212 AC: 1022 AN: 4820

European-Finnish (FIN) AF: 0.171 AC: 1809 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9705 AN: 67996

Other (OTH) AF: 0.145 AC: 307 AN: 2110

Alfa AF: 0.142 Hom.: 2791

Bravo AF: 0.141

Asia WGS AF: 0.227 AC: 791 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.4
DANN	Benign	0.68
PhyloP100		0.34

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1883633; hg19: chr6-53429272;