chr21-42886775-G-A

Variant names:

• chr21-42886775-G-A
• rs1009829
• ENST00000460259.1:n.413-26G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000460259.1(NDUFV3):​n.413-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,240 control chromosomes in the GnomAD database, including 33,205 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (33204 hom., cov: 34)
  • Exomes 𝑓: 0.75 (1 hom.)
• Consequence: NDUFV3 ENST00000460259.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.882
• Publications: 5 publications found

Genes affected

NDUFV3 (HGNC:7719): (NADH:ubiquinone oxidoreductase subunit V3) The protein encoded by this gene is one of at least forty-one subunits that make up the NADH-ubiquinone oxidoreductase complex. This complex is part of the mitochondrial respiratory chain and serves to catalyze the rotenone-sensitive oxidation of NADH and the reduction of ubiquinone. The encoded protein is one of three proteins found in the flavoprotein fraction of the complex. The specific function of the encoded protein is unknown. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

WDR4 (HGNC:12756): (WD repeat domain 4) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene is excluded as a candidate for a form of nonsyndromic deafness (DFNB10), but is still a candidate for other disorders mapped to 21q22.3 as well as for the development of Down syndrome phenotypes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

WDR4 Gene-Disease associations (from GenCC):

• microcephaly, growth deficiency, seizures, and brain malformations

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Galloway-Mowat syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Galloway-Mowat syndrome 6

  Inheritance: AR Classification: LIMITED Submitted by: G2P

LOC105372817 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR4	XM_024452048.2	c.-350+4618C>T		intron_variant	Intron 2 of 11		XP_024307816.1
LOC105372817	XR_937765.3	n.235-26G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFV3	ENST00000460259.1	n.413-26G>A		intron_variant	Intron 2 of 5	2

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97779 AN: 152118 Hom.: 33151 Cov.: 34

Gnomad AFR AF: 0.857

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.582

GnomAD4 exome AF: 0.750 AC: 3 AN: 4 Hom.: 1 Cov.: 0 AF XY: 0.750 AC XY: 3 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.643 AC: 97883 AN: 152236 Hom.: 33204 Cov.: 34 AF XY: 0.639 AC XY: 47530 AN XY: 74428

African (AFR) AF: 0.857 AC: 35620 AN: 41562

American (AMR) AF: 0.443 AC: 6769 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1967 AN: 3468

East Asian (EAS) AF: 0.339 AC: 1755 AN: 5180

South Asian (SAS) AF: 0.558 AC: 2695 AN: 4828

European-Finnish (FIN) AF: 0.626 AC: 6637 AN: 10594

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40478 AN: 67994

Other (OTH) AF: 0.585 AC: 1238 AN: 2116

Alfa AF: 0.642 Hom.: 4446

Bravo AF: 0.634

Asia WGS AF: 0.462 AC: 1613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.51
DANN	Benign	0.44
PhyloP100		-0.88

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1009829; hg19: chr21-44306885;