rs74752435

chr15-101178745-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014918.5(CHSY1):c.1052A>G(p.Lys351Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,614,188 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (35 hom., cov: 33)
  • Exomes 𝑓: 0.016 (323 hom.)
• Consequence: CHSY1 NM_014918.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.31

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014885366).
• BP6: Variant 15-101178745-T-C is Benign according to our data. Variant chr15-101178745-T-C is described in ClinVar as [Benign]. Clinvar id is 466168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-101178745-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHSY1	NM_014918.5	c.1052A>G	p.Lys351Arg	missense_variant	3/3	ENST00000254190.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHSY1	ENST00000254190.4	c.1052A>G	p.Lys351Arg	missense_variant	3/3	1	NM_014918.5	P1
CHSY1	ENST00000560766.1	n.385A>G		non_coding_transcript_exon_variant	3/3	4
CHSY1	ENST00000561414.1	n.421A>G		non_coding_transcript_exon_variant	2/2	4
CHSY1	ENST00000543813.2	c.*367A>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2508 AN: 152192 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.0758

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0168

GnomAD3 exomes AF: 0.0250 AC: 6286 AN: 251486 Hom.: 170 AF XY: 0.0231 AC XY: 3135 AN XY: 135916

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.0317

Gnomad EAS exome AF: 0.0798

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0156 AC: 22736 AN: 1461878 Hom.: 323 Cov.: 35 AF XY: 0.0152 AC XY: 11071 AN XY: 727238

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.0547

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.0650

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0165 AC: 2513 AN: 152310 Hom.: 35 Cov.: 33 AF XY: 0.0176 AC XY: 1311 AN XY: 74490

Gnomad4 AFR AF: 0.00599

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.0756

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.0265

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0154 Hom.: 51

Bravo AF: 0.0172

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0116 AC: 100

ExAC AF: 0.0215 AC: 2611

Asia WGS AF: 0.0370 AC: 128 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 08, 2019	- -

Temtamy preaxial brachydactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.52	N
MutationTaster	Benign	0.90	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.047
Sift	Benign	0.40	T
Sift4G	Benign	0.57	T
Polyphen		0.0030	B
Vest4		0.024
MPC		0.26
ClinPred		0.0038	T
GERP RS		4.5
Varity_R		0.036
gMVP		0.28

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: rs74752435; hg19: chr15-101718950; COSMIC: COSV54251976;