5-157460212-C-A

Position:

• chr5-157460212-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The ENST00000517951.5(ADAM19):​c.*1741+28053G>T variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,486,492 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (5 hom.)
• Consequence: ADAM19 ENST00000517951.5 intron, NMD_transcript
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0490

Genes affected

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-157460212-C-A is Benign according to our data. Variant chr5-157460212-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 352505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NIPAL4	NM_001099287.2			upstream_gene_variant		ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2			upstream_gene_variant			NP_001165763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946.8			upstream_gene_variant		1	NM_001099287.2	ENSP00000311687	P1

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00157 AC: 141 AN: 89838 Hom.: 0 AF XY: 0.00188 AC XY: 92 AN XY: 48904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000442

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00468

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000672

Gnomad OTH exome AF: 0.00351

GnomAD4 exome AF: 0.000653 AC: 871 AN: 1334162 Hom.: 5 Cov.: 32 AF XY: 0.000763 AC XY: 499 AN XY: 653790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00387

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.000644 AC XY: 48 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00238 Hom.: 2

Bravo AF: 0.000654

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.92

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: rs374248640; hg19: chr5-156887220;