Genetic Variant CHSY1:p.Pro787Thr (chr15-101177438-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014918.5(CHSY1):c.2359C>A(p.Pro787Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P787S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHSY1
NM_014918.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.14

Publications

0 publications found

Variant links:

Genes affected

CHSY1 (HGNC:17198): (chondroitin sulfate synthase 1) This gene encodes a member of the chondroitin N-acetylgalactosaminyltransferase family. These enzymes possess dual glucuronyltransferase and galactosaminyltransferase activity and play critical roles in the biosynthesis of chondroitin sulfate, a glycosaminoglycan involved in many biological processes including cell proliferation and morphogenesis. Decreased expression of this gene may play a role in colorectal cancer, and mutations in this gene are a cause of temtamy preaxial brachydactyly syndrome. [provided by RefSeq, Dec 2011]

CHSY1 Gene-Disease associations (from GenCC):

temtamy preaxial brachydactyly syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

CHSY1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14099836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHSY1	NM_014918.5 link	c.2359C>A	p.Pro787Thr	missense_variant	Exon 3 of 3	ENST00000254190.4	NP_055733.2	Q86X52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHSY1	ENST00000254190.4 link	c.2359C>A	p.Pro787Thr	missense_variant	Exon 3 of 3	1	NM_014918.5	ENSP00000254190.3	Q86X52
CHSY1	ENST00000543813.2 link	n.*1674C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2		ENSP00000496160.1	A0A2R8Y7B7
CHSY1	ENST00000543813.2 link	n.*1674C>A		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000496160.1	A0A2R8Y7B7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461288

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111842

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0058

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

M_CAP

Benign

0.0071

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

6.1

PrimateAI

Benign

0.38

PROVEAN

Benign

0.060

REVEL

Benign

0.18

Sift

Benign

0.23

Sift4G

Benign

1.0

Polyphen

0.80

Vest4

0.34

MutPred

0.13

Gain of helix (P = 0.0325);

MVP

0.24

MPC

0.36

ClinPred

0.58

GERP RS

5.9

Varity_R

0.044

gMVP

0.42

Mutation Taster

=79/21

polymorphism

(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

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15-101177438-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over