5-178242343-T-G

Variant summary

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

The NM_173465.4(COL23A1):c.1492A>C(p.Lys498Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: COL23A1 NM_173465.4 missense, splice_region
• Scores: Splicing: ADA: 0.001011
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

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.1492A>C	p.Lys498Gln	missense_variant, splice_region_variant	26/29	ENST00000390654.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL23A1	ENST00000390654.8	c.1492A>C	p.Lys498Gln	missense_variant, splice_region_variant	26/29	5	NM_173465.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

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

Aug 02, 2021

The c.1492A>C (p.K498Q) alteration is located in exon 26 (coding exon 26) of the COL23A1 gene. This alteration results from a A to C substitution at nucleotide position 1492, causing the lysine (K) at amino acid position 498 to be replaced by a glutamine (Q). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Benign	0.92
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.48	N;.
MutationTaster	Benign	0.54	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.014	D;.
Sift4G	Uncertain	0.044	D;T
Polyphen		0.43	B;.
Vest4		0.42
MutPred		0.46		Loss of methylation at K498 (P = 0.002);.;
MVP		0.91
MPC		0.49
ClinPred		0.72	D
GERP RS		3.2
Varity_R		0.24
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.022
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

LitVar

Other links and lift over

dbSNP: rs897150476; hg19: chr5-177669344;