ENST00000519499.2:c.-2319G>T

Variant names:

• chr5-157460094-C-A
• rs555788817
• ENST00000519499.2:c.-2319G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000519499.2(ENSG00000285868):​c.-2319G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,270,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ENSG00000285868 ENST00000519499.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913
• Publications: 0 publications found

Genes affected

ENSG00000285868 (HGNC:):

NIPAL4-DT (HGNC:55542): (NIPAL4 divergent transcript)

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]

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]

NIPAL4 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lamellar ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000519499.2. 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
	NIPAL4-DT	NR_136204.1		n.7G>T		non_coding_transcript_exon	Exon 1 of 4
	NIPAL4-DT	NR_136205.1		n.7G>T		non_coding_transcript_exon	Exon 1 of 3
	NIPAL4	NM_001099287.2	MANE Select	c.-227C>A		upstream_gene	N/A	NP_001092757.2	Q0D2K0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000285868	ENST00000519499.2	TSL:3	c.-2319G>T		5_prime_UTR	Exon 1 of 6	ENSP00000496943.1
	ADAM19	ENST00000517951.5	TSL:2	n.*1741+28171G>T		intron	N/A	ENSP00000428376.1	E5RIS2
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.-227C>A		upstream_gene	N/A	ENSP00000311687.8	Q0D2K0-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000268 AC: 3 AN: 1118690 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 545882

African (AFR) AF: 0.00 AC: 0 AN: 21178

American (AMR) AF: 0.00 AC: 0 AN: 14206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16478

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29322

South Asian (SAS) AF: 0.00 AC: 0 AN: 55140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3348

European-Non Finnish (NFE) AF: 0.00000113 AC: 1 AN: 888396

Other (OTH) AF: 0.0000214 AC: 1 AN: 46756

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

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

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		0.91
PromoterAI		-0.077	Neutral

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

Other links and lift over

dbSNP: rs555788817; hg19: chr5-156887102;