chrX-43949084-A-G

Variant names:

• chrX-43949084-A-G
• rs3747350
• NM_000266.4:c.*715T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000266.4(NDP):​c.*715T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 112,049 control chromosomes in the GnomAD database, including 2 homozygotes. There are 59 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., 59 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NDP NM_000266.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.792
• 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 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy 2, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Norrie disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• exudative vitreoretinopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• persistent hyperplastic primary vitreous

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant X-43949084-A-G is Benign according to our data. Variant chrX-43949084-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 255688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00162 (182/112049) while in subpopulation EAS AF = 0.0301 (107/3558). AF 95% confidence interval is 0.0255. There are 2 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 182 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.*715T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.*715T>C		3_prime_UTR_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.*715T>C		3_prime_UTR_variant	Exon 4 of 4			ENSP00000495811.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 182 AN: 111999 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0000974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00679

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.00444

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00132

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1355 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 253

African (AFR) AF: 0.00 AC: 0 AN: 3

American (AMR) AF: 0.00 AC: 0 AN: 352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 63

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 882

Other (OTH) AF: 0.00 AC: 0 AN: 41

GnomAD4 genome AF: 0.00162 AC: 182 AN: 112049 Hom.: 2 Cov.: 23 AF XY: 0.00172 AC XY: 59 AN XY: 34233

African (AFR) AF: 0.0000972 AC: 3 AN: 30878

American (AMR) AF: 0.00312 AC: 33 AN: 10565

Ashkenazi Jewish (ASJ) AF: 0.00679 AC: 18 AN: 2652

East Asian (EAS) AF: 0.0301 AC: 107 AN: 3558

South Asian (SAS) AF: 0.00446 AC: 12 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6053

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53220

Other (OTH) AF: 0.00131 AC: 2 AN: 1530

Alfa AF: 0.000676 Hom.: 28

Bravo AF: 0.00211

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.35
CADD	Benign	8.3
DANN	Benign	0.86
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism

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: rs3747350; hg19: chrX-43808330;