chr15-40953666-G-A

Position:

• chr15-40953666-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024111.6(CHAC1):​c.83G>A​(p.Gly28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHAC1 NM_024111.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.995

Genes affected

CHAC1 (HGNC:28680): (ChaC glutathione specific gamma-glutamylcyclotransferase 1) This gene encodes a member of the gamma-glutamylcyclotransferase family of proteins. The encoded protein has been shown to promote neuronal differentiation by deglycination of the Notch receptor, which prevents receptor maturation and inhibits Notch signaling. This protein may also play a role in the unfolded protein response, and in regulation of glutathione levels and oxidative balance in the cell. Elevated expression of this gene may indicate increased risk of cancer recurrence among breast and ovarian cancer patients. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073076755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAC1	NM_024111.6	c.83G>A	p.Gly28Asp	missense_variant	1/3	ENST00000617768.5
CHAC1	NM_001142776.4	c.83G>A	p.Gly28Asp	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAC1	ENST00000617768.5	c.83G>A	p.Gly28Asp	missense_variant	1/3	1	NM_024111.6	P1
CHAC1	ENST00000444189.7	c.83G>A	p.Gly28Asp	missense_variant	1/4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456548 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 724906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.209G>A (p.G70D) alteration is located in exon 1 (coding exon 1) of the CHAC1 gene. This alteration results from a G to A substitution at nucleotide position 209, causing the glycine (G) at amino acid position 70 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.2
DANN	Benign	0.89
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.58	T;T;.;.
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
REVEL	Benign	0.022
Sift4G	Benign	0.45	.;.;T;.
Vest4		0.21
MutPred		0.31		.;.;Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);
MVP		0.25
MPC		0.74
ClinPred		0.050	T
GERP RS		2.5
Varity_R		0.081

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: rs776155734; hg19: chr15-41245864;