5-157472917-C-T

Variant names:

• chr5-157472917-C-T
• rs61743233
• NM_001099287.2:c.1172C>T

Variant summary

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

The NM_001099287.2(NIPAL4):​c.1172C>T​(p.Ser391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,524,446 control chromosomes in the GnomAD database, including 4,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (907 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3246 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.645
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014172196).
• BP6: Variant 5-157472917-C-T is Benign according to our data. Variant chr5-157472917-C-T is described in ClinVar as Benign. ClinVar VariationId is 257435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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.1172C>T	p.Ser391Leu	missense	Exon 6 of 6	NP_001092757.2
	NIPAL4	NM_001172292.2		c.1115C>T	p.Ser372Leu	missense	Exon 5 of 5	NP_001165763.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NIPAL4	ENST00000311946.8	TSL:1 MANE Select	c.1172C>T	p.Ser391Leu	missense	Exon 6 of 6	ENSP00000311687.8
	NIPAL4	ENST00000435489.7	TSL:2	c.1115C>T	p.Ser372Leu	missense	Exon 5 of 5	ENSP00000406456.3
	ADAM19	ENST00000517951.5	TSL:2	n.*1741+15348G>A		intron	N/A	ENSP00000428376.1

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13592 AN: 152066 Hom.: 903 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.0630 AC: 11150 AN: 176962 AF XY: 0.0633

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0550

Gnomad OTH exome AF: 0.0640

GnomAD4 exome AF: 0.0602 AC: 82657 AN: 1372262 Hom.: 3246 Cov.: 32 AF XY: 0.0616 AC XY: 41453 AN XY: 672580

African (AFR) AF: 0.194 AC: 5923 AN: 30572

American (AMR) AF: 0.0481 AC: 1497 AN: 31116

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1273 AN: 20280

East Asian (EAS) AF: 0.000976 AC: 38 AN: 38946

South Asian (SAS) AF: 0.115 AC: 8142 AN: 70890

European-Finnish (FIN) AF: 0.0291 AC: 1450 AN: 49798

Middle Eastern (MID) AF: 0.104 AC: 555 AN: 5314

European-Non Finnish (NFE) AF: 0.0559 AC: 59740 AN: 1068900

Other (OTH) AF: 0.0716 AC: 4039 AN: 56446

GnomAD4 genome AF: 0.0895 AC: 13615 AN: 152184 Hom.: 907 Cov.: 32 AF XY: 0.0887 AC XY: 6598 AN XY: 74400

African (AFR) AF: 0.186 AC: 7703 AN: 41474

American (AMR) AF: 0.0608 AC: 930 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5188

South Asian (SAS) AF: 0.109 AC: 527 AN: 4824

European-Finnish (FIN) AF: 0.0238 AC: 252 AN: 10606

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0543 AC: 3695 AN: 68016

Other (OTH) AF: 0.114 AC: 240 AN: 2112

Alfa AF: 0.0686 Hom.: 962

Bravo AF: 0.0950

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0553 AC: 213

ESP6500AA AF: 0.168 AC: 638

ESP6500EA AF: 0.0538 AC: 445

ExAC AF: 0.0620 AC: 7264

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive congenital ichthyosis 6 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.65
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.30
Sift	Benign	0.39	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.075
MPC		0.25
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.37
Mutation Taster		=95/5	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: rs61743233; hg19: chr5-156899925; COSMIC: COSV57436334; COSMIC: COSV57436334;