1-161074389-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_030916.3(NECTIN4):c.1001-16G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00922 in 1,613,978 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (103 hom.)
• Consequence: NECTIN4 NM_030916.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.548

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-161074389-C-T is Benign according to our data. Variant chr1-161074389-C-T is described in ClinVar as [Benign]. Clinvar id is 1612942.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0065 (990/152220) while in subpopulation NFE AF= 0.0108 (735/67992). AF 95% confidence interval is 0.0102. There are 4 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NECTIN4	NM_030916.3	c.1001-16G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000368012.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NECTIN4	ENST00000368012.4	c.1001-16G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_030916.3	P1

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 990 AN: 152102 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00593 AC: 1478 AN: 249390 Hom.: 11 AF XY: 0.00557 AC XY: 751 AN XY: 134920

Gnomad AFR exome AF: 0.00143

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00943

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00950 AC: 13883 AN: 1461758 Hom.: 103 Cov.: 32 AF XY: 0.00915 AC XY: 6651 AN XY: 727188

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.00975

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00757

GnomAD4 genome AF: 0.00650 AC: 990 AN: 152220 Hom.: 4 Cov.: 32 AF XY: 0.00576 AC XY: 429 AN XY: 74438

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00662 Hom.: 1

Bravo AF: 0.00590

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	16
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41270003; hg19: chr1-161044179;