15-40953761-T-C

Variant names:

• chr15-40953761-T-C
• rs143317285
• NM_024111.6:c.178T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP4

The NM_024111.6(CHAC1):​c.178T>C​(p.Tyr60His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,599,902 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: CHAC1 NM_024111.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, BayesDel_noAF, Cadd, Eigen, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.3894573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAC1	NM_024111.6	c.178T>C	p.Tyr60His	missense_variant	Exon 1 of 3	ENST00000617768.5	NP_077016.3
CHAC1	NM_001142776.4	c.178T>C	p.Tyr60His	missense_variant	Exon 1 of 4		NP_001136248.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAC1	ENST00000617768.5	c.178T>C	p.Tyr60His	missense_variant	Exon 1 of 3	1	NM_024111.6	ENSP00000484644.2
CHAC1	ENST00000444189.7	c.178T>C	p.Tyr60His	missense_variant	Exon 1 of 4	1		ENSP00000395466.3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.000661

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000470 AC: 109 AN: 231994 Hom.: 0 AF XY: 0.000483 AC XY: 62 AN XY: 128466

Gnomad AFR exome AF: 0.000143

Gnomad AMR exome AF: 0.000790

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000789

Gnomad NFE exome AF: 0.000708

Gnomad OTH exome AF: 0.000516

GnomAD4 exome AF: 0.000672 AC: 973 AN: 1447628 Hom.: 1 Cov.: 33 AF XY: 0.000626 AC XY: 451 AN XY: 720576

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000498

Gnomad4 NFE exome AF: 0.000814

Gnomad4 OTH exome AF: 0.000415

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74466

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000694 Hom.: 0

Bravo AF: 0.000597

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000355 AC: 3

ExAC AF: 0.000466 AC: 56

EpiCase AF: 0.000709

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304T>C (p.Y102H) alteration is located in exon 1 (coding exon 1) of the CHAC1 gene. This alteration results from a T to C substitution at nucleotide position 304, causing the tyrosine (Y) at amino acid position 102 to be replaced by a histidine (H). 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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;.;.
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	-0.11	T
PrimateAI	Uncertain	0.77	T
REVEL	Pathogenic	0.66
Sift4G	Pathogenic	0.0	.;.;D;.
Vest4		0.87
MVP		0.89
MPC		1.7
ClinPred		0.15	T
GERP RS		5.4
Varity_R		0.41

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: rs143317285; hg19: chr15-41245959;