Genetic Variant NT5DC1:c.529+8248C>G (chr6-116126193-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_152729.3(NT5DC1):c.529+8248C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 152,106 control chromosomes in the GnomAD database, including 5,754 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5752 hom., cov: 32)

Exomes 𝑓: 0.20 ( 2 hom. )

Consequence

NT5DC1
NM_152729.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.16

Publications

4 publications found

Variant links:

Genes affected

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:

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 Gene-Disease associations (from GenCC):

Schmid metaphyseal chondrodysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

COL10A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NT5DC1	NM_152729.3 link	c.529+8248C>G		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2	Q5TFE4-1Q9H2R1
COL10A1	NM_000493.4 link	c.-156G>C		upstream_gene_variant		ENST00000651968.1	NP_000484.2	Q03692A0A650AXN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NT5DC1	ENST00000319550.9 link	c.529+8248C>G		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3		Q5TFE4-1
COL10A1	ENST00000651968.1 link	c.-156G>C		upstream_gene_variant			NM_000493.4	ENSP00000498802.1		Q03692

Frequencies

GnomAD3 genomes

AF:

0.264

AC:

40103

AN:

151934

Hom.:

5746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.336

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.00462

Gnomad SAS

AF:

0.0855

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.369

Gnomad NFE

AF:

0.268

Gnomad OTH

AF:

0.281

GnomAD4 exome

AF:

0.204

AC:

AN:

Hom.:

AF XY:

0.229

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.196

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0159933), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.264

AC:

40138

AN:

152052

Hom.:

5752

Cov.:

AF XY:

0.256

AC XY:

19014

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.336

AC:

13918

AN:

41448

American (AMR)

AF:

0.226

AC:

3445

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

1026

AN:

3470

East Asian (EAS)

AF:

0.00463

AC:

AN:

5180

South Asian (SAS)

AF:

0.0855

AC:

412

AN:

4816

European-Finnish (FIN)

AF:

0.209

AC:

2218

AN:

10590

Middle Eastern (MID)

AF:

0.356

AC:

104

AN:

292

European-Non Finnish (NFE)

AF:

0.268

AC:

18236

AN:

67970

Other (OTH)

AF:

0.277

AC:

584

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1453

2906

4358

5811

7264

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.121

Hom.:

194

Bravo

AF:

0.273

Asia WGS

AF:

0.0680

AC:

239

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

2.2

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over