5-157463148-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001099287.2(NIPAL4):c.92A>G(p.Asn31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,613,980 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.30

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028746426).
• BP6: Variant 5-157463148-A-G is Benign according to our data. Variant chr5-157463148-A-G is described in ClinVar as [Benign]. Clinvar id is 776087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00449 (683/152278) while in subpopulation AFR AF= 0.0156 (648/41550). AF 95% confidence interval is 0.0146. There are 5 homozygotes in gnomad4. There are 320 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPAL4	NM_001099287.2	c.92A>G	p.Asn31Ser	missense_variant	2/6	ENST00000311946.8
NIPAL4	NM_001172292.2	c.92A>G	p.Asn31Ser	missense_variant	2/5
NIPAL4	XM_011534552.2	c.-218A>G		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPAL4	ENST00000311946.8	c.92A>G	p.Asn31Ser	missense_variant	2/6	1	NM_001099287.2	P1

Frequencies

GnomAD3 genomes AF: 0.00450 AC: 684 AN: 152160 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00115 AC: 286 AN: 249256 Hom.: 2 AF XY: 0.000932 AC XY: 126 AN XY: 135222

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000455 AC: 665 AN: 1461702 Hom.: 5 Cov.: 31 AF XY: 0.000411 AC XY: 299 AN XY: 727136

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.00449 AC: 683 AN: 152278 Hom.: 5 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74452

Gnomad4 AFR AF: 0.0156

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000759 Hom.: 2

Bravo AF: 0.00502

ESP6500AA AF: 0.0180 AC: 73

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	1.9
Dann	Benign	0.66
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.55	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.39	N;N
REVEL	Benign	0.20
Sift	Benign	0.58	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0	B;B
Vest4		0.076
MVP		0.17
MPC		0.22
ClinPred		0.0096	T
GERP RS		3.4
Varity_R		0.027
gMVP		0.22

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: rs138368479; hg19: chr5-156890156;