X-43949789-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000266.4(NDP):c.*10C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,164,724 control chromosomes in the GnomAD database, including 10 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., 168 hem., cov: 22)
  • Exomes 𝑓: 0.00057 (5 hom. 154 hem.)
• Consequence: NDP NM_000266.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0610

Genes affected

NDP (HGNC:7678): (norrin cystine knot growth factor NDP) This gene encodes a secreted protein with a cystein-knot motif that activates the Wnt/beta-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. Mutations in this gene result in Norrie disease and X-linked exudative vitreoretinopathy. [provided by RefSeq, Feb 2009]

NDP-AS1 (HGNC:40395): (NDP antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-43949789-G-C is Benign according to our data. Variant chrX-43949789-G-C is described in ClinVar as [Benign]. Clinvar id is 167324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00573 (643/112134) while in subpopulation AFR AF= 0.0202 (623/30839). AF 95% confidence interval is 0.0189. There are 5 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.*10C>G		3_prime_UTR_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.58G>C		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.*10C>G		3_prime_UTR_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.58G>C		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.*10C>G		3_prime_UTR_variant	4/4			P1
NDP	ENST00000470584.1	n.456C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 640 AN: 112079 Hom.: 5 Cov.: 22 AF XY: 0.00488 AC XY: 167 AN XY: 34231

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00332

GnomAD3 exomes AF: 0.00130 AC: 154 AN: 118798 Hom.: 1 AF XY: 0.000879 AC XY: 36 AN XY: 40968

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000454

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000697

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.000593

GnomAD4 exome AF: 0.000567 AC: 597 AN: 1052590 Hom.: 5 Cov.: 28 AF XY: 0.000451 AC XY: 154 AN XY: 341634

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.000709

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000200

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000857

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.00573 AC: 643 AN: 112134 Hom.: 5 Cov.: 22 AF XY: 0.00490 AC XY: 168 AN XY: 34296

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.00113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00328

Alfa AF: 0.000740 Hom.: 2

Bravo AF: 0.00659

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 30, 2014

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.2
Dann	Benign	0.76

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: rs140653237; hg19: chrX-43809035;