5-157460218-CTCGC-T

Variant names:

• chr5-157460218-CTCGC-T
• NM_001099287.2:c.-103_-99delCTCGCinsT

Variant summary

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

The NM_001099287.2(NIPAL4):​c.-103_-99delCTCGCinsT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NIPAL4 NM_001099287.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

NIPAL4 (HGNC:28018): (NIPA like domain containing 4) This gene likely encodes a membrane receptor. Mutations in this gene have been associated with autosomal recessive congenital ichthyosis. [provided by RefSeq, Feb 2010]

ADAM19 (HGNC:197): (ADAM metallopeptidase domain 19) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This member is a type I transmembrane protein and serves as a marker for dendritic cell differentiation. It has been demonstrated to be an active metalloproteinase, which may be involved in normal physiological processes such as cell migration, cell adhesion, cell-cell and cell-matrix interactions, and signal transduction. It is proposed to play a role in pathological processes, such as cancer, inflammatory diseases, renal diseases, and Alzheimer's disease. [provided by RefSeq, May 2013]

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 rank	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.-103_-99delCTCGCinsT		5_prime_UTR_variant	Exon 1 of 6	ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.-103_-99delCTCGCinsT		5_prime_UTR_variant	Exon 1 of 5		NP_001165763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946	c.-103_-99delCTCGCinsT		5_prime_UTR_variant	Exon 1 of 6	1	NM_001099287.2	ENSP00000311687.8

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NIPAL4 c.84_88delinsT (p.Ser29AlafsX133) results in a frameshift in the first exon of the longest protein isoform (NM_001099287.1) of NIPAL4. However, the variant is located in the untranslated mRNA region (c.-103_-99delinsT) upstream of the initiation codon in the shorter (canonical) protein isoform (NM_001099287.2) of NIPAL4. The variant was absent in 125568 control chromosomes (gnomAD). To our knowledge, no occurrence of c.84_88delinsT in individuals affected with Lamellar Ichthyosis and no experimental evidence demonstrating its impact on protein function have been reported. However, upstream from this position, a start-loss variant affecting the longer isoform, c.2T>C (p.Met1?), has been reported in a homozygous patient (PMID: 31347739; this variant would correspond to c.-185T>C in the shorter isoform). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr5-156887226;