X-43949785-C-T

Variant names:

• chrX-43949785-C-T
• rs73475744
• NM_000266.4:c.*14G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000266.4(NDP):​c.*14G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,162,669 control chromosomes in the GnomAD database, including 48 homozygotes. There are 853 hemizygotes in GnomAD. 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 0.014 (25 hom., 442 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (23 hom. 411 hem.)
• Consequence: NDP NM_000266.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.899
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-43949785-C-T is Benign according to our data. Variant chrX-43949785-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 588627.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (1546/112221) while in subpopulation AFR AF = 0.0481 (1483/30857). AF 95% confidence interval is 0.046. There are 25 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1546 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.*14G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.54C>T		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.*14G>A		3_prime_UTR_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1
NDP-AS1	ENST00000435093.1	n.54C>T		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1	n.460G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
NDP	ENST00000647044.1	c.*14G>A		3_prime_UTR_variant	Exon 4 of 4			ENSP00000495811.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 1533 AN: 112167 Hom.: 25 Cov.: 23

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00423

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00993

GnomAD2 exomes AF: 0.00365 AC: 431 AN: 118142 AF XY: 0.00252

Gnomad AFR exome AF: 0.0497

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000861

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00144 AC: 1517 AN: 1050448 Hom.: 23 Cov.: 28 AF XY: 0.00121 AC XY: 411 AN XY: 339968

African (AFR) AF: 0.0499 AC: 1246 AN: 24964

American (AMR) AF: 0.00252 AC: 71 AN: 28127

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18623

East Asian (EAS) AF: 0.00 AC: 0 AN: 27298

South Asian (SAS) AF: 0.000140 AC: 7 AN: 49842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37780

Middle Eastern (MID) AF: 0.000980 AC: 4 AN: 4080

European-Non Finnish (NFE) AF: 0.0000147 AC: 12 AN: 815416

Other (OTH) AF: 0.00399 AC: 177 AN: 44318

GnomAD4 genome AF: 0.0138 AC: 1546 AN: 112221 Hom.: 25 Cov.: 23 AF XY: 0.0129 AC XY: 442 AN XY: 34377

African (AFR) AF: 0.0481 AC: 1483 AN: 30857

American (AMR) AF: 0.00413 AC: 44 AN: 10653

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6147

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53252

Other (OTH) AF: 0.00981 AC: 15 AN: 1529

Alfa AF: 0.00108 Hom.: 5

Bravo AF: 0.0161

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

History of neurodevelopmental disorder Uncertain:1

Jan 10, 2013

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

not provided Benign:1

Dec 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.0
DANN	Benign	0.88
PhyloP100		0.90
Mutation Taster		=100/0	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: rs73475744; hg19: chrX-43809031;