6-116126193-C-G

Variant names:

• chr6-116126193-C-G
• rs9488843
• NM_152729.3:c.529+8248C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.16
• Publications: 4 publications found

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]

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)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152729.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5DC1	NM_152729.3	MANE Select	c.529+8248C>G		intron	N/A	NP_689942.2
	COL10A1	NM_001424106.1		c.-15-686G>C		intron	N/A	NP_001411035.1
	COL10A1	NM_001424107.1		c.-15-686G>C		intron	N/A	NP_001411036.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5DC1	ENST00000319550.9	TSL:1 MANE Select	c.529+8248C>G		intron	N/A	ENSP00000326858.3
	NT5DC1	ENST00000880964.1		c.529+8248C>G		intron	N/A	ENSP00000551023.1
	NT5DC1	ENST00000880963.1		c.529+8248C>G		intron	N/A	ENSP00000551022.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40103 AN: 151934 Hom.: 5746 Cov.: 32

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: 11 AN: 54 Hom.: 2 AF XY: 0.229 AC XY: 11 AN XY: 48

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.196 AC: 9 AN: 46

Other (OTH) AF: 0.250 AC: 1 AN: 4

⚠️ 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.

GnomAD4 genome AF: 0.264 AC: 40138 AN: 152052 Hom.: 5752 Cov.: 32 AF XY: 0.256 AC XY: 19014 AN XY: 74354

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: 24 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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.67
PhyloP100		2.2
PromoterAI		0.019	Neutral
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9488843; hg19: chr6-116447356; COSMIC: COSV54574434; COSMIC: COSV54574434;