6-116119756-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000493.4(COL10A1):c.*317T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 227,868 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: COL10A1 NM_000493.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.121

Genes affected

COL10A1 (HGNC:2185): (collagen type X alpha 1 chain) This gene encodes the alpha chain of type X collagen, a short chain collagen expressed by hypertrophic chondrocytes during endochondral ossification. Unlike type VIII collagen, the other short chain collagen, type X collagen is a homotrimer. Mutations in this gene are associated with Schmid type metaphyseal chondrodysplasia (SMCD) and Japanese type spondylometaphyseal dysplasia (SMD). [provided by RefSeq, Jul 2008]

NT5DC1 (HGNC:21556): (5'-nucleotidase domain containing 1) While the exact function of the protein encoded by this gene is not known, it belongs to the 5'(3')-deoxyribonucleotidase family. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-116119756-A-T is Benign according to our data. Variant chr6-116119756-A-T is described in ClinVar as [Benign]. Clinvar id is 355081.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00279 (414/148492) while in subpopulation SAS AF= 0.0469 (218/4644). AF 95% confidence interval is 0.0418. There are 9 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 409 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL10A1	NM_000493.4	c.*317T>A		3_prime_UTR_variant	3/3	ENST00000651968.1
NT5DC1	NM_152729.3	c.529+1811A>T		intron_variant		ENST00000319550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL10A1	ENST00000651968.1	c.*317T>A		3_prime_UTR_variant	3/3		NM_000493.4	P1
NT5DC1	ENST00000319550.9	c.529+1811A>T		intron_variant		1	NM_152729.3	P1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 409 AN: 148382 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00181

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00507

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.000606

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00297

GnomAD4 exome AF: 0.00227 AC: 180 AN: 79376 Hom.: 3 Cov.: 0 AF XY: 0.00248 AC XY: 100 AN XY: 40398

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.000733

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.00276

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00279 AC: 414 AN: 148492 Hom.: 9 Cov.: 32 AF XY: 0.00355 AC XY: 257 AN XY: 72404

Gnomad4 AFR AF: 0.000173

Gnomad4 AMR AF: 0.00181

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00508

Gnomad4 SAS AF: 0.0469

Gnomad4 FIN AF: 0.000606

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00490

Alfa AF: 0.00227 Hom.: 0

Asia WGS AF: 0.0410 AC: 140 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.23
Dann	Benign	0.14

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: rs553227989; hg19: chr6-116440919; COSMIC: COSV99683998; COSMIC: COSV99683998;