rs199422217

Variant names:

• chr5-157468728-C-A
• rs199422217
• NM_001099287.2:c.341C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-157468728-C-A
• chr5-157468728-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001099287.2(NIPAL4):​c.341C>A​(p.Ala114Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000775 in 152,310 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 2.03
• Publications: 24 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: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 5-157468728-C-A is Pathogenic according to our data. Variant chr5-157468728-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38465208). . Strength limited to SUPPORTING due to the PP5.

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.341C>A	p.Ala114Asp	missense	Exon 4 of 6	NP_001092757.2	Q0D2K0-1
	NIPAL4	NM_001172292.2		c.284C>A	p.Ala95Asp	missense	Exon 3 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.341C>A	p.Ala114Asp	missense	Exon 4 of 6	ENSP00000311687.8	Q0D2K0-1
	NIPAL4	ENST00000435489.7	TSL:2	c.284C>A	p.Ala95Asp	missense	Exon 3 of 5	ENSP00000406456.3	Q0D2K0-2
	NIPAL4	ENST00000519150.1	TSL:5	n.*40C>A		non_coding_transcript_exon	Exon 5 of 7	ENSP00000430810.1	H0YC31

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000652 AC: 160 AN: 245384 AF XY: 0.000628

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000678

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00115 AC: 1671 AN: 1456064 Hom.: 1 Cov.: 29 AF XY: 0.00109 AC XY: 789 AN XY: 724712

African (AFR) AF: 0.0000899 AC: 3 AN: 33382

American (AMR) AF: 0.000314 AC: 14 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000488 AC: 42 AN: 86036

European-Finnish (FIN) AF: 0.000324 AC: 17 AN: 52442

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.00139 AC: 1536 AN: 1107942

Other (OTH) AF: 0.000948 AC: 57 AN: 60096

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74492

African (AFR) AF: 0.000241 AC: 10 AN: 41562

American (AMR) AF: 0.000458 AC: 7 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68022

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

Alfa AF: 0.000869 Hom.: 0

Bravo AF: 0.000763

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00192 AC: 16

ExAC AF: 0.000662 AC: 80

EpiCase AF: 0.000929

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Autosomal recessive congenital ichthyosis 6 (14)
7	-	-	not provided (7)
1	-	-	Autosomal recessive congenital ichthyosis (2)
1	-	-	Ichthyosis and erythrokeratoderma (1)
1	-	-	Lamellar ichthyosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		0.74	P
Vest4		0.86
MVP		0.61
MPC		1.1
ClinPred		0.051	T
GERP RS		3.9
Varity_R		0.71
gMVP		0.89
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199422217; hg19: chr5-156895736;