17-41930778-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBS1_SupportingBS2

The NM_031421.5(ODAD4):c.55G>A(p.Glu19Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,609,000 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000054 ( 2 hom. )

Consequence

ODAD4
NM_031421.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.80

Variant links:

Genes affected

ODAD4 (HGNC:25280): (outer dynein arm docking complex subunit 4) This gene encodes a tetratricopeptide repeat domain-containing protein that localizes to ciliary axonmenes and plays a role in the docking of the outer dynein arm to cilia. Mutations in this gene cause severely reduced ciliary motility and the disorder CILD35 (ciliary dyskinesia,primary, 35). Primary ciliary dyskinesia is often associated with recurrent respiratory infections, immotile spermatozoa, and situs inversus; an inversion in left-right body symmetry. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2017]

ODAD4 links:

ACLY (HGNC:115): (ATP citrate lyase) ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

ACLY links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen [when max_spliceai, MetaRNN, REVEL was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.028528154).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000632 (96/151856) while in subpopulation AFR AF= 0.00167 (69/41428). AF 95% confidence interval is 0.00135. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD4	NM_031421.5 link	c.55G>A	p.Glu19Lys	missense_variant	Exon 1 of 12	ENST00000377540.6	NP_113609.1	Q96NG3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ODAD4	ENST00000377540.6 link	c.55G>A	p.Glu19Lys	missense_variant	Exon 1 of 12	1	NM_031421.5	ENSP00000478589.1	Q96NG3-1
ODAD4	ENST00000591658.5 link	n.55G>A		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000477931.1	A0A087WTJ8
ODAD4	ENST00000593239.5 link	n.55G>A		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000484975.1	A0A087X2G9
ACLY	ENST00000592970.1 link	c.-448C>T		upstream_gene_variant		4		ENSP00000468705.1	K7ESG8

Frequencies

GnomAD3 genomes

AF:

0.000633

AC:

AN:

151748

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.00

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.000141

AC:

AN:

241418

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

130868

show subpopulations

Gnomad AFR exome

AF:

0.00175

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000916

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000535

AC:

AN:

1457144

Hom.:

Cov.:

AF XY:

0.0000414

AC XY:

AN XY:

724426

show subpopulations

Gnomad4 AFR exome

AF:

0.000868

Gnomad4 AMR exome

AF:

0.000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000632

AC:

AN:

151856

Hom.:

Cov.:

AF XY:

0.000661

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00167

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.0000700

Hom.:

Bravo

AF:

0.00106

ESP6500AA

AF:

0.00108

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000182

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55G>A (p.E19K) alteration is located in exon 1 (coding exon 1) of the TTC25 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the glutamic acid (E) at amino acid position 19 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.063

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.40

PrimateAI

Uncertain

0.77

REVEL

Benign

0.27

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.61

MVP

0.44

ClinPred

0.21

GERP RS

5.7

Varity_R

0.36

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over