ENST00000519499.2:c.-2319G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000519499.2(ENSG00000285868):​c.-2319G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,271,008 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: ENSG00000285868 ENST00000519499.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-157460094-C-T is Benign according to our data. Variant chr5-157460094-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 352503.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000807 (123/152332) while in subpopulation SAS AF = 0.0242 (117/4832). AF 95% confidence interval is 0.0207. There are 3 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 gene

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>A		non_coding_transcript_exon	Exon 1 of 4
	NIPAL4-DT	NR_136205.1		n.7G>A		non_coding_transcript_exon	Exon 1 of 3
	NIPAL4	NM_001099287.2	MANE Select	c.-227C>T		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>A		5_prime_UTR	Exon 1 of 6	ENSP00000496943.1
	ADAM19	ENST00000517951.5	TSL:2	n.*1741+28171G>A		intron	N/A	ENSP00000428376.1	E5RIS2
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.-227C>T		upstream_gene	N/A	ENSP00000311687.8	Q0D2K0-1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152214 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00219 AC: 78 AN: 35636 AF XY: 0.00270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.00110 AC: 1230 AN: 1118676 Hom.: 23 Cov.: 16 AF XY: 0.00162 AC XY: 886 AN XY: 545868

African (AFR) AF: 0.0000472 AC: 1 AN: 21178

American (AMR) AF: 0.0000704 AC: 1 AN: 14206

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 29322

South Asian (SAS) AF: 0.0206 AC: 1135 AN: 55136

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

Middle Eastern (MID) AF: 0.000299 AC: 1 AN: 3348

European-Non Finnish (NFE) AF: 0.0000191 AC: 17 AN: 888386

Other (OTH) AF: 0.00160 AC: 75 AN: 46756

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152332 Hom.: 3 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74484

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.0242 AC: 117 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000178

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive congenital ichthyosis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		0.91
PromoterAI		-0.22	Neutral
Mutation Taster		=100/0	polymorphism

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;