5-157460125-A-G

Variant names:

• chr5-157460125-A-G
• rs1105282
• ENST00000517951.5:n.*1741+28140T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000517951.5(ADAM19):​n.*1741+28140T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,410,364 control chromosomes in the GnomAD database, including 90,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11148 hom., cov: 33)
  • Exomes 𝑓: 0.35 (79010 hom.)
• Consequence: ADAM19 ENST00000517951.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.658
• Publications: 18 publications found

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]

ENSG00000285868 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 5-157460125-A-G is Benign according to our data. Variant chr5-157460125-A-G is described in ClinVar as Benign. ClinVar VariationId is 257433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000517951.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	NM_001099287.2	MANE Select	c.-196A>G		upstream_gene	N/A	NP_001092757.2
	NIPAL4	NM_001172292.2		c.-196A>G		upstream_gene	N/A	NP_001165763.2
	NIPAL4-DT	NR_136204.1		n.-25T>C		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM19	ENST00000517951.5	TSL:2	n.*1741+28140T>C		intron	N/A	ENSP00000428376.1
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.-196A>G		upstream_gene	N/A	ENSP00000311687.8
	ENSG00000285868	ENST00000519499.2	TSL:3	c.-2350T>C		upstream_gene	N/A	ENSP00000496943.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57139 AN: 151908 Hom.: 11131 Cov.: 33

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.368 AC: 17039 AN: 46260 AF XY: 0.371

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.711

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.348 AC: 438407 AN: 1258338 Hom.: 79010 Cov.: 28 AF XY: 0.348 AC XY: 212080 AN XY: 609606

African (AFR) AF: 0.385 AC: 9309 AN: 24156

American (AMR) AF: 0.317 AC: 5027 AN: 15840

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 6312 AN: 17434

East Asian (EAS) AF: 0.671 AC: 20396 AN: 30412

South Asian (SAS) AF: 0.348 AC: 20534 AN: 58996

European-Finnish (FIN) AF: 0.345 AC: 15202 AN: 44118

Middle Eastern (MID) AF: 0.376 AC: 1468 AN: 3902

European-Non Finnish (NFE) AF: 0.338 AC: 341534 AN: 1011910

Other (OTH) AF: 0.361 AC: 18625 AN: 51570

GnomAD4 genome AF: 0.376 AC: 57188 AN: 152026 Hom.: 11148 Cov.: 33 AF XY: 0.379 AC XY: 28202 AN XY: 74318

African (AFR) AF: 0.392 AC: 16255 AN: 41508

American (AMR) AF: 0.360 AC: 5510 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3472

East Asian (EAS) AF: 0.720 AC: 3698 AN: 5136

South Asian (SAS) AF: 0.362 AC: 1746 AN: 4824

European-Finnish (FIN) AF: 0.346 AC: 3657 AN: 10584

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23762 AN: 67892

Other (OTH) AF: 0.374 AC: 790 AN: 2114

Alfa AF: 0.363 Hom.: 1591

Bravo AF: 0.373

Asia WGS AF: 0.537 AC: 1868 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive congenital ichthyosis 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.66
PromoterAI		-0.45	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs1105282; hg19: chr5-156887133; COSMIC: COSV100357189; COSMIC: COSV100357189;