rs138368479

Variant names:

• chr5-157463148-A-G
• rs138368479
• NM_001099287.2:c.92A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099287.2. 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	NM_001099287.2	MANE Select	c.92A>G	p.Asn31Ser	missense	Exon 2 of 6	NP_001092757.2	Q0D2K0-1
	NIPAL4	NM_001172292.2		c.92A>G	p.Asn31Ser	missense	Exon 2 of 5	NP_001165763.2	Q0D2K0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.92A>G	p.Asn31Ser	missense	Exon 2 of 6	ENSP00000311687.8	Q0D2K0-1
	NIPAL4	ENST00000521390.5	TSL:1	n.197A>G		non_coding_transcript_exon	Exon 2 of 4
	NIPAL4	ENST00000435489.7	TSL:2	c.92A>G	p.Asn31Ser	missense	Exon 2 of 5	ENSP00000406456.3	Q0D2K0-2

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

GnomAD2 exomes AF: 0.00115 AC: 286 AN: 249256 AF XY: 0.000932

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 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

African (AFR) AF: 0.0173 AC: 579 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111860

Other (OTH) AF: 0.000696 AC: 42 AN: 60374

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

African (AFR) AF: 0.0156 AC: 648 AN: 41550

American (AMR) AF: 0.00176 AC: 27 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00180 Hom.: 6

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.032	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.55	N
PhyloP100		2.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.20
Sift	Benign	0.58	T
Sift4G	Benign	0.48	T
Polyphen		0.0	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
Mutation Taster		=97/3	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: rs138368479; hg19: chr5-156890156;