NM_004273.5:c.-274G>T

Variant names:

• chr10-71964528-G-T
• rs146305825
• NM_004273.5:c.-274G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004273.5(CHST3):​c.-274G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 152,002 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (111 hom., cov: 33)
  • Exomes 𝑓: 0.025 (0 hom.)
• Consequence: CHST3 NM_004273.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -2.48
• Publications: 0 publications found

Genes affected

CHST3 (HGNC:1971): (carbohydrate sulfotransferase 3) This gene encodes an enzyme which catalyzes the sulfation of chondroitin, a proteoglycan found in the extracellular matrix and most cells which is involved in cell migration and differentiation. Mutations in this gene are associated with spondylepiphyseal dysplasia and humerospinal dysostosis. [provided by RefSeq, Mar 2009]

CHST3 Gene-Disease associations (from GenCC):

• spondyloepiphyseal dysplasia with congenital joint dislocations

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-71964528-G-T is Benign according to our data. Variant chr10-71964528-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 300549.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004273.5. 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
	CHST3	NM_004273.5	MANE Select	c.-274G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_004264.2
	CHST3	NM_004273.5	MANE Select	c.-274G>T		5_prime_UTR	Exon 1 of 3	NP_004264.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST3	ENST00000373115.5	TSL:1 MANE Select	c.-274G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000362207.4	Q7LGC8
	CHST3	ENST00000373115.5	TSL:1 MANE Select	c.-274G>T		5_prime_UTR	Exon 1 of 3	ENSP00000362207.4	Q7LGC8

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2841 AN: 151856 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.0651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0250 AC: 1 AN: 40 Hom.: 0 Cov.: 0 AF XY: 0.0417 AC XY: 1 AN XY: 24

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0188 AC: 2855 AN: 151962 Hom.: 111 Cov.: 33 AF XY: 0.0178 AC XY: 1322 AN XY: 74298

African (AFR) AF: 0.0653 AC: 2701 AN: 41376

American (AMR) AF: 0.00628 AC: 96 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67946

Other (OTH) AF: 0.0138 AC: 29 AN: 2106

Alfa AF: 0.00412 Hom.: 4

Bravo AF: 0.0217

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Larsen syndrome (1)
-	-	1	Skeletal dysplasia (1)
-	-	1	Spondyloepiphyseal dysplasia congenita (1)
-	-	1	Spondyloepiphyseal dysplasia with congenital joint dislocations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.49
PhyloP100		-2.5
PromoterAI		-0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs146305825; hg19: chr10-73724286;