chr1-152910212-G-A

Position:

• chr1-152910212-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005547.4(IVL):​c.415G>A​(p.Val139Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IVL NM_005547.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.109

Genes affected

IVL (HGNC:6187): (involucrin) Involucrin, a component of the keratinocyte crosslinked envelope, is found in the cytoplasm and crosslinked to membrane proteins by transglutaminase. This gene is mapped to 1q21, among calpactin I light chain, trichohyalin, profillaggrin, loricrin, and calcyclin. [provided by RefSeq, Jul 2008]

ENSG00000289062 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06776568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVL	NM_005547.4	c.415G>A	p.Val139Ile	missense_variant	2/2	ENST00000368764.4	NP_005538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IVL	ENST00000368764.4	c.415G>A	p.Val139Ile	missense_variant	2/2	2	NM_005547.4	ENSP00000357753.3
ENSG00000289062	ENST00000686895.2	n.94+2829C>T		intron_variant
ENSG00000289062	ENST00000702923.1	n.238+2661C>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 26, 2024

The c.415G>A (p.V139I) alteration is located in exon 2 (coding exon 1) of the IVL gene. This alteration results from a G to A substitution at nucleotide position 415, causing the valine (V) at amino acid position 139 to be replaced by an isoleucine (I). 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	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.93
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.036
Sift	Benign	0.085	T
Sift4G	Benign	0.20	T
Polyphen		0.48	P
Vest4		0.048
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0483);
MVP		0.072
MPC		0.0052
ClinPred		0.12	T
GERP RS		0.27
Varity_R		0.062
gMVP		0.0035

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-152882688;