1-152910373-G-T

Position:

• chr1-152910373-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005547.4(IVL):​c.576G>T​(p.Gln192His) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IVL NM_005547.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.528

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.118955165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IVL	NM_005547.4	c.576G>T	p.Gln192His	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.576G>T	p.Gln192His	missense_variant	2/2	2	NM_005547.4	ENSP00000357753.3
ENSG00000289062	ENST00000686895.2	n.94+2668C>A		intron_variant
ENSG00000289062	ENST00000702923.1	n.238+2500C>A		intron_variant

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000449 AC: 6 AN: 1335066 Hom.: 0 Cov.: 33 AF XY: 0.00000612 AC XY: 4 AN XY: 653834

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: 0.0000910

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

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

Dec 07, 2021

The c.576G>T (p.Q192H) alteration is located in exon 2 (coding exon 1) of the IVL gene. This alteration results from a G to T substitution at nucleotide position 576, causing the glutamine (Q) at amino acid position 192 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.6
DANN	Benign	0.42
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.050
Sift	Benign	0.29	T
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.078
MutPred		0.15		Gain of loop (P = 0.2045);
MVP		0.36
MPC		0.0049
ClinPred		0.22	T
GERP RS		-4.1
Varity_R		0.034
gMVP		0.043

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

LitVar

Other links and lift over

dbSNP: rs200516479; hg19: chr1-152882849;