6-116119755-T-A

Variant names:

• chr6-116119755-T-A
• rs566235360
• NM_000493.4:c.*318A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000493.4(COL10A1):​c.*318A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 243,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: COL10A1 NM_000493.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.33
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000555 (84/151402) while in subpopulation AFR AF = 0.0015 (62/41332). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.*318A>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+1810T>A		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1	c.*318A>T		3_prime_UTR_variant	Exon 3 of 3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+1810T>A		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes AF: 0.000542 AC: 82 AN: 151286 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000218 AC: 20 AN: 91784 Hom.: 0 Cov.: 0 AF XY: 0.000150 AC XY: 7 AN XY: 46746

African (AFR) AF: 0.00182 AC: 5 AN: 2742

American (AMR) AF: 0.00 AC: 0 AN: 4742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3116

East Asian (EAS) AF: 0.000150 AC: 1 AN: 6684

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4802

European-Finnish (FIN) AF: 0.000465 AC: 2 AN: 4300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 380

European-Non Finnish (NFE) AF: 0.000118 AC: 7 AN: 59154

Other (OTH) AF: 0.000512 AC: 3 AN: 5864

GnomAD4 genome AF: 0.000555 AC: 84 AN: 151402 Hom.: 0 Cov.: 33 AF XY: 0.000595 AC XY: 44 AN XY: 74000

African (AFR) AF: 0.00150 AC: 62 AN: 41332

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4780

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67698

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000759 Hom.: 0

Bravo AF: 0.000604

Asia WGS AF: 0.00174 AC: 6 AN: 3464

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia, Schmid type Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.44
DANN	Benign	0.30
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism

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: rs566235360; hg19: chr6-116440918; COSMIC: COSV99684176; COSMIC: COSV99684176;