1-161072867-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_030916.3(NECTIN4):c.1327C>T(p.Arg443Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00105 in 1,613,354 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: NECTIN4 NM_030916.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: 4.34

Genes affected

NECTIN4 (HGNC:19688): (nectin cell adhesion molecule 4) This gene encodes a member of the nectin family. The encoded protein contains two immunoglobulin-like (Ig-like) C2-type domains and one Ig-like V-type domain. It is involved in cell adhesion through trans-homophilic and -heterophilic interactions. It is a single-pass type I membrane protein. The soluble form is produced by proteolytic cleavage at the cell surface by the metalloproteinase ADAM17/TACE. The secreted form is found in both breast tumor cell lines and breast tumor patients. Mutations in this gene are the cause of ectodermal dysplasia-syndactyly syndrome type 1, an autosomal recessive disorder. Alternatively spliced transcript variants have been found but the full-length nature of the variant has not been determined.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013679683).
• BP6: Variant 1-161072867-G-A is Benign according to our data. Variant chr1-161072867-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418440.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, not_provided=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00104 (158/152290) while in subpopulation AMR AF= 0.0019 (29/15302). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECTIN4	NM_030916.3	c.1327C>T	p.Arg443Cys	missense_variant	9/9	ENST00000368012.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECTIN4	ENST00000368012.4	c.1327C>T	p.Arg443Cys	missense_variant	9/9	1	NM_030916.3	P1
NECTIN4	ENST00000486694.1	n.137C>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00100 AC: 250 AN: 249442 Hom.: 0 AF XY: 0.00102 AC XY: 138 AN XY: 134866

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00389

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000330

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00105 AC: 1535 AN: 1461064 Hom.: 0 Cov.: 31 AF XY: 0.00103 AC XY: 752 AN XY: 726780

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00437

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000337

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74464

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00136 Hom.: 1

Bravo AF: 0.00123

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000873 AC: 106

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	The R443C variant in the PVRL4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R443C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R443C as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

NECTIN4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ectodermal dysplasia-syndactyly syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.76
MPC		1.6
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.49

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: rs1537044; hg19: chr1-161042657;