Genetic Variant NDP:p.Arg121Arg (chrX-43949838-C-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_000266.4(NDP):c.363G>T(p.Arg121Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,185,066 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 7 hem. )

Consequence

NDP
NM_000266.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

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 links:

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

NDP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant X-43949838-C-A is Benign according to our data. Variant chrX-43949838-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1529811.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.21 with no splicing effect.

BS2

High AC in GnomAdExome4 at 15 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.363G>T	p.Arg121Arg	synonymous_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.107C>A		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDP	ENST00000642620.1 link	c.363G>T	p.Arg121Arg	synonymous_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.363G>T	p.Arg121Arg	synonymous_variant	Exon 4 of 4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.107C>A		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1 link	n.407G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111791

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1073275

Hom.:

Cov.:

AF XY:

0.0000200

AC XY:

AN XY:

349865

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25832

American (AMR)

AF:

0.00

AC:

AN:

31125

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18892

East Asian (EAS)

AF:

0.00

AC:

AN:

28755

South Asian (SAS)

AF:

0.00

AC:

AN:

50991

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38872

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4110

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

829492

Other (OTH)

AF:

0.00

AC:

AN:

45206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111791

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33979

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30706

American (AMR)

AF:

0.00

AC:

AN:

10543

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2668

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6087

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53159

Other (OTH)

AF:

0.00

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.37

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

1.2

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

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X-43949838-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over