5-157460192-C-T

Variant names:

• chr5-157460192-C-T
• rs557034321
• ENST00000517951.5:n.*1741+28073G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000517951.5(ADAM19):​n.*1741+28073G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,470,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: ADAM19 ENST00000517951.5 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.12
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014621019).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	NM_001099287.2	MANE Select	c.-129C>T		upstream_gene	N/A	NP_001092757.2	Q0D2K0-1
	NIPAL4	NM_001172292.2		c.-129C>T		upstream_gene	N/A	NP_001165763.2	Q0D2K0-2
	NIPAL4-DT	NR_136204.1		n.-92G>A		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM19	ENST00000517951.5	TSL:2	n.*1741+28073G>A		intron	N/A	ENSP00000428376.1	E5RIS2
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.-129C>T		upstream_gene	N/A	ENSP00000311687.8	Q0D2K0-1
	ENSG00000285868	ENST00000519499.2	TSL:3	c.-2417G>A		upstream_gene	N/A	ENSP00000496943.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000492 AC: 4 AN: 81274 AF XY: 0.0000461

Gnomad AFR exome AF: 0.000320

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000834 AC: 11 AN: 1318590 Hom.: 0 Cov.: 32 AF XY: 0.00000931 AC XY: 6 AN XY: 644318

African (AFR) AF: 0.0000756 AC: 2 AN: 26460

American (AMR) AF: 0.00 AC: 0 AN: 24206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19440

East Asian (EAS) AF: 0.000153 AC: 5 AN: 32728

South Asian (SAS) AF: 0.00 AC: 0 AN: 65576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4812

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1045888

Other (OTH) AF: 0.0000737 AC: 4 AN: 54270

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74492

African (AFR) AF: 0.0000240 AC: 1 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000189 AC: 2

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.28
Sift	Uncertain	0.011	D
Sift4G	Benign	0.75	T
Polyphen		0.39	B
Vest4		0.15
MutPred		0.067		Gain of phosphorylation at P20 (P = 0.0191)
MVP		0.36
MPC		0.43
ClinPred		0.064	T
GERP RS		2.6
PromoterAI		-0.51	Under-expression
Varity_R		0.049
gMVP		0.13

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: rs557034321; hg19: chr5-156887200;