Genetic Variant CHAC1:p.Tyr60His (chr15-40953761-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.46

Publications

4 publications found

Variant links:

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]

CHAC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, REVEL, REVEL [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.3894573).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024111.6. 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
	CHAC1	NM_024111.6	MANE Select	c.178T>C	p.Tyr60His	missense	Exon 1 of 3	NP_077016.3	Q9BUX1-1
	CHAC1	NM_001142776.4		c.178T>C	p.Tyr60His	missense	Exon 1 of 4	NP_001136248.2	Q9BUX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAC1	ENST00000617768.5	TSL:1 MANE Select	c.178T>C	p.Tyr60His	missense	Exon 1 of 3	ENSP00000484644.2	Q9BUX1-1
	CHAC1	ENST00000444189.7	TSL:1	c.178T>C	p.Tyr60His	missense	Exon 1 of 4	ENSP00000395466.3	Q9BUX1-2

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000470

AC:

109

AN:

231994

AF XY:

0.000483

show subpopulations

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 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.:

Cov.:

AF XY:

0.000626

AC XY:

451

AN XY:

720576

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33432

American (AMR)

AF:

0.000784

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.0000498

AC:

AN:

40142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000814

AC:

905

AN:

1111404

Other (OTH)

AF:

0.000415

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000433

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41552

American (AMR)

AF:

0.000915

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000662

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000665

Hom.:

Bravo

AF:

0.000597

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000355

AC:

ExAC

AF:

0.000466

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.39

MetaSVM

Uncertain

-0.11

PhyloP100

7.5

PrimateAI

Uncertain

0.77

REVEL

Pathogenic

0.66

Sift4G

Pathogenic

0.0

Vest4

0.87

MVP

0.89

MPC

1.7

ClinPred

0.15

GERP RS

5.4

PromoterAI

0.019

Neutral

(source)

Varity_R

0.41

Mutation Taster

=49/51

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over