5-178256921-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173465.4(COL23A1):c.782C>T(p.Pro261Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL23A1 NM_173465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

Genes affected

COL23A1 (HGNC:22990): (collagen type XXIII alpha 1 chain) COL23A1 is a member of the transmembrane collagens, a subfamily of the nonfibrillar collagens that contain a single pass hydrophobic transmembrane domain (Banyard et al., 2003 [PubMed 12644459]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL23A1	NM_173465.4	c.782C>T	p.Pro261Leu	missense_variant	14/29	ENST00000390654.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL23A1	ENST00000390654.8	c.782C>T	p.Pro261Leu	missense_variant	14/29	5	NM_173465.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246320 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461158 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726828

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2023

The c.782C>T (p.P261L) alteration is located in exon 14 (coding exon 14) of the COL23A1 gene. This alteration results from a C to T substitution at nucleotide position 782, causing the proline (P) at amino acid position 261 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.27	B;.
Vest4		0.26
MutPred		0.27		Loss of glycosylation at P261 (P = 0.0961);.;
MVP		0.90
MPC		0.26
ClinPred		0.39	T
GERP RS		2.7
Varity_R		0.13
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs754179891; hg19: chr5-177683922;