6-116119744-GT-G

Variant names:

• chr6-116119744-GT-G
• rs371155563
• NM_000493.4:c.*328delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000493.4(COL10A1):​c.*328delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 212,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (0 hom.)
• Consequence: COL10A1 NM_000493.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.606
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000239 (33/138068) while in subpopulation EAS AF = 0.00108 (5/4638). AF 95% confidence interval is 0.000424. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.*328delA		3_prime_UTR_variant	Exon 3 of 3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+1810delT		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.*328delA		3_prime_UTR_variant	Exon 3 of 3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+1810delT		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3

Frequencies

GnomAD3 genomes AF: 0.000239 AC: 33 AN: 138008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000213

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00108

Gnomad SAS AF: 0.000237

Gnomad FIN AF: 0.000114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000224

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00576 AC: 427 AN: 74118 Hom.: 0 Cov.: 0 AF XY: 0.00565 AC XY: 213 AN XY: 37680

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

African (AFR) AF: 0.00291 AC: 6 AN: 2062

American (AMR) AF: 0.00612 AC: 24 AN: 3920

Ashkenazi Jewish (ASJ) AF: 0.00448 AC: 11 AN: 2456

East Asian (EAS) AF: 0.00944 AC: 48 AN: 5086

South Asian (SAS) AF: 0.00638 AC: 28 AN: 4392

European-Finnish (FIN) AF: 0.00637 AC: 22 AN: 3456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00552 AC: 264 AN: 47820

Other (OTH) AF: 0.00519 AC: 24 AN: 4624

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000239 AC: 33 AN: 138068 Hom.: 0 Cov.: 32 AF XY: 0.000164 AC XY: 11 AN XY: 67042

African (AFR) AF: 0.000239 AC: 9 AN: 37594

American (AMR) AF: 0.000213 AC: 3 AN: 14092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3222

East Asian (EAS) AF: 0.00108 AC: 5 AN: 4638

South Asian (SAS) AF: 0.000239 AC: 1 AN: 4192

European-Finnish (FIN) AF: 0.000114 AC: 1 AN: 8774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000224 AC: 14 AN: 62536

Other (OTH) AF: 0.00 AC: 0 AN: 1896

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metaphyseal chondrodysplasia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.61
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: rs371155563; hg19: chr6-116440907;