1-153261218-A-ACTCCGGCGGCGGCGGCTC

Position:

• chr1-153261218-A-ACTCCGGCGGCGGCGGCTC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BS2_Supporting

The NM_000427.3(LORICRIN):​c.275_276insCGGCGGCGGCTCCTCCGG​(p.Gly92_Gly93insGlyGlyGlySerSerGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,198,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G92G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: LORICRIN NM_000427.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.512

Genes affected

LORICRIN (HGNC:6663): (loricrin cornified envelope precursor protein) This gene encodes loricrin, a major protein component of the cornified cell envelope found in terminally differentiated epidermal cells. Mutations in this gene are associated with Vohwinkel's syndrome and progressive symmetric erythrokeratoderma, both inherited skin diseases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000427.3.
• BS2: High AC in GnomAdExome4 at 15 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LORICRIN	NM_000427.3	c.275_276insCGGCGGCGGCTCCTCCGG	p.Gly92_Gly93insGlyGlyGlySerSerGly	disruptive_inframe_insertion	2/2	ENST00000368742.4	NP_000418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LORICRIN	ENST00000368742.4	c.275_276insCGGCGGCGGCTCCTCCGG	p.Gly92_Gly93insGlyGlyGlySerSerGly	disruptive_inframe_insertion	2/2	1	NM_000427.3	ENSP00000357731.3

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.0000125 AC: 15 AN: 1198662 Hom.: 0 Cov.: 45 AF XY: 0.0000120 AC XY: 7 AN XY: 584218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000367

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.0000613

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2023

This variant, c.275_276insCGGCGGCGGCTCCTCCGG, results in the insertion of 6 amino acid(s) of the LOR protein (p.Gly95_Gly100dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with LOR-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1658772846; hg19: chr1-153233694;