Genetic Variant COL10A1:c.*328dupA (chr6-116119744-G-GT) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000493.4(COL10A1):c.*328dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 210,906 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.053 ( 0 hom. )

Consequence

COL10A1
NM_000493.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.606

Publications

0 publications found

Variant links:

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]

COL10A1 links:

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]

NT5DC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00263 (363/137978) while in subpopulation AFR AF = 0.00426 (160/37588). AF 95% confidence interval is 0.00372. There are 1 homozygotes in GnomAd4. There are 178 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 363 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4 link	c.*328dupA		3_prime_UTR_variant	Exon 3 of 3	ENST00000651968.1	NP_000484.2	Q03692A0A650AXN9
NT5DC1	NM_152729.3 link	c.529+1810dupT		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2	Q5TFE4-1Q9H2R1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1 link	c.*328dupA		3_prime_UTR_variant	Exon 3 of 3		NM_000493.4	ENSP00000498802.1		Q03692
NT5DC1	ENST00000319550.9 link	c.529+1810dupT		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3		Q5TFE4-1

Frequencies

GnomAD3 genomes

AF:

0.00263

AC:

363

AN:

137918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00192

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000861

Gnomad SAS

AF:

0.00119

Gnomad FIN

AF:

0.00229

Gnomad MID

AF:

0.0204

Gnomad NFE

AF:

0.00154

Gnomad OTH

AF:

0.00265

GnomAD4 exome

AF:

0.0531

AC:

3874

AN:

72928

Hom.:

Cov.:

AF XY:

0.0532

AC XY:

1970

AN XY:

37052

show subpopulations

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

African (AFR)

AF:

0.0464

AC:

AN:

2028

American (AMR)

AF:

0.0659

AC:

252

AN:

3822

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

138

AN:

2408

East Asian (EAS)

AF:

0.0500

AC:

251

AN:

5020

South Asian (SAS)

AF:

0.0436

AC:

189

AN:

4338

European-Finnish (FIN)

AF:

0.0429

AC:

147

AN:

3426

Middle Eastern (MID)

AF:

0.0582

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0544

AC:

2557

AN:

47046

Other (OTH)

AF:

0.0504

AC:

229

AN:

4548

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.278

Heterozygous variant carriers

347

694

1040

1387

1734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00263

AC:

363

AN:

137978

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

178

AN XY:

66980

show subpopulations

African (AFR)

AF:

0.00426

AC:

160

AN:

37588

American (AMR)

AF:

0.00192

AC:

AN:

14078

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3220

East Asian (EAS)

AF:

0.000863

AC:

AN:

4636

South Asian (SAS)

AF:

0.00119

AC:

AN:

4190

European-Finnish (FIN)

AF:

0.00229

AC:

AN:

8742

Middle Eastern (MID)

AF:

0.0182

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00154

AC:

AN:

62504

Other (OTH)

AF:

0.00264

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000246

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism

(source)

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

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6-116119744-G-GT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over