5-157472861-T-C

Variant names:

• chr5-157472861-T-C
• rs4704870
• NM_001099287.2:c.1116T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099287.2(NIPAL4):​c.1116T>C​(p.Val372Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,573,488 control chromosomes in the GnomAD database, including 736,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72854 hom., cov: 30)
  • Exomes 𝑓: 0.97 (663158 hom.)
• Consequence: NIPAL4 NM_001099287.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.748
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-157472861-T-C is Benign according to our data. Variant chr5-157472861-T-C is described in ClinVar as Benign. ClinVar VariationId is 257434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.748 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 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.1116T>C	p.Val372Val	synonymous	Exon 6 of 6	NP_001092757.2
	NIPAL4	NM_001172292.2		c.1059T>C	p.Val353Val	synonymous	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.1116T>C	p.Val372Val	synonymous	Exon 6 of 6	ENSP00000311687.8
	NIPAL4	ENST00000435489.7	TSL:2	c.1059T>C	p.Val353Val	synonymous	Exon 5 of 5	ENSP00000406456.3
	ADAM19	ENST00000517951.5	TSL:2	n.*1741+15404A>G		intron	N/A	ENSP00000428376.1

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148788 AN: 152094 Hom.: 72793 Cov.: 30

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.990

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.982

GnomAD2 exomes AF: 0.978 AC: 216322 AN: 221182 AF XY: 0.978

Gnomad AFR exome AF: 0.994

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 0.980

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.982

Gnomad NFE exome AF: 0.966

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.966 AC: 1372852 AN: 1421276 Hom.: 663158 Cov.: 42 AF XY: 0.967 AC XY: 677775 AN XY: 700934

African (AFR) AF: 0.995 AC: 32648 AN: 32824

American (AMR) AF: 0.985 AC: 42164 AN: 42790

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 22621 AN: 23098

East Asian (EAS) AF: 1.00 AC: 39294 AN: 39296

South Asian (SAS) AF: 0.990 AC: 77853 AN: 78624

European-Finnish (FIN) AF: 0.980 AC: 50648 AN: 51676

Middle Eastern (MID) AF: 0.997 AC: 5565 AN: 5580

European-Non Finnish (NFE) AF: 0.960 AC: 1045088 AN: 1088778

Other (OTH) AF: 0.972 AC: 56971 AN: 58610

GnomAD4 genome AF: 0.978 AC: 148908 AN: 152212 Hom.: 72854 Cov.: 30 AF XY: 0.980 AC XY: 72903 AN XY: 74410

African (AFR) AF: 0.993 AC: 41216 AN: 41516

American (AMR) AF: 0.986 AC: 15094 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3395 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 0.993 AC: 4793 AN: 4826

European-Finnish (FIN) AF: 0.983 AC: 10411 AN: 10590

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65566 AN: 68026

Other (OTH) AF: 0.982 AC: 2067 AN: 2104

Alfa AF: 0.970 Hom.: 101830

Bravo AF: 0.979

Asia WGS AF: 0.995 AC: 3462 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive congenital ichthyosis 6 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.4
DANN	Benign	0.67
PhyloP100		0.75
Mutation Taster		=38/62	disease causing

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: rs4704870; hg19: chr5-156899869; COSMIC: COSV108034872; COSMIC: COSV108034872;