6-116125413-A-T

Variant names:

• chr6-116125413-A-T
• rs1064583
• NM_000493.4:c.80T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000493.4(COL10A1):​c.80T>A​(p.Met27Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M27T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL10A1 NM_000493.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72
• Publications: 58 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000493.4. 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
	COL10A1	NM_000493.4	MANE Select	c.80T>A	p.Met27Lys	missense	Exon 2 of 3	NP_000484.2
	NT5DC1	NM_152729.3	MANE Select	c.529+7468A>T		intron	N/A	NP_689942.2
	COL10A1	NM_001424106.1		c.80T>A	p.Met27Lys	missense	Exon 2 of 3	NP_001411035.1	A0A650AXN9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL10A1	ENST00000651968.1	MANE Select	c.80T>A	p.Met27Lys	missense	Exon 2 of 3	ENSP00000498802.1	Q03692
	COL10A1	ENST00000243222.8	TSL:1	c.80T>A	p.Met27Lys	missense	Exon 2 of 3	ENSP00000243222.4	Q03692
	COL10A1	ENST00000327673.4	TSL:1	c.80T>A	p.Met27Lys	missense	Exon 1 of 2	ENSP00000327368.4	Q03692

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	14
DANN	Benign	0.90
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.56	N
REVEL	Uncertain	0.34
Sift	Benign	0.40	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.75		Gain of disorder (P = 0.0135)
MVP		0.85
MPC		0.0075
ClinPred		0.60	D
GERP RS		6.1
PromoterAI		-0.027	Neutral
Varity_R		0.15
gMVP		0.58
Mutation Taster		=99/1	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: rs1064583; hg19: chr6-116446576;