8-120168161-T-G

Variant names:

• chr8-120168161-T-G
• rs1815973062
• NM_021110.4:c.350T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021110.4(COL14A1):​c.350T>G​(p.Ile117Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,453,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I117T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL14A1 NM_021110.4 missense, splice_region
• Scores: Splicing: ADA: 0.2746
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.27
• Publications: 0 publications found

Genes affected

COL14A1 (HGNC:2191): (collagen type XIV alpha 1 chain) This gene encodes the alpha chain of type XIV collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XIV collagen interacts with the fibril surface and is involved in the regulation of fibrillogenesis. [provided by RefSeq, Jan 2013]

COL14A1 Gene-Disease associations (from GenCC):

• punctate palmoplantar keratoderma type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary palmoplantar keratoderma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021110.4. 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
	COL14A1	NM_021110.4	MANE Select	c.350T>G	p.Ile117Ser	missense splice_region	Exon 5 of 48	NP_066933.1	Q05707-1
	COL14A1	NM_001413492.1		c.350T>G	p.Ile117Ser	missense splice_region	Exon 5 of 48	NP_001400421.1
	COL14A1	NM_001413490.1		c.350T>G	p.Ile117Ser	missense splice_region	Exon 5 of 48	NP_001400419.1	Q05707-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL14A1	ENST00000297848.8	TSL:5 MANE Select	c.350T>G	p.Ile117Ser	missense splice_region	Exon 5 of 48	ENSP00000297848.3	Q05707-1
	COL14A1	ENST00000432943.6	TSL:1	n.584T>G		splice_region non_coding_transcript_exon	Exon 5 of 27
	COL14A1	ENST00000498051.6	TSL:1	n.350T>G		splice_region non_coding_transcript_exon	Exon 8 of 23	ENSP00000428851.1	Q4G0W3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453048 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 723488

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

African (AFR) AF: 0.00 AC: 0 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 44178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105488

Other (OTH) AF: 0.00 AC: 0 AN: 60006

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.15	T
Polyphen		0.92	P
Vest4		0.79
MutPred		0.28		Loss of stability (P = 0.0105)
MVP		0.96
MPC		0.89
ClinPred		0.80	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.78
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.27
dbscSNV1_RF	Benign	0.42
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: rs1815973062; hg19: chr8-121180400; COSMIC: COSV99918252;