17-41935693-G-A

Variant names:

• chr17-41935693-G-A
• rs34520854
• NM_031421.5:c.341G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031421.5(ODAD4):​c.341G>A​(p.Arg114Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000917 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ODAD4 NM_031421.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058097214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD4	NM_031421.5	c.341G>A	p.Arg114Gln	missense_variant	Exon 3 of 12	ENST00000377540.6	NP_113609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ODAD4	ENST00000377540.6	c.341G>A	p.Arg114Gln	missense_variant	Exon 3 of 12	1	NM_031421.5	ENSP00000478589.1
ODAD4	ENST00000591658.5	n.341G>A		non_coding_transcript_exon_variant	Exon 3 of 10	5		ENSP00000477931.1
ODAD4	ENST00000585530.1	n.*61+150G>A		intron_variant	Intron 2 of 3	3		ENSP00000479460.1
ODAD4	ENST00000593239.5	n.*61+150G>A		intron_variant	Intron 3 of 5	3		ENSP00000484975.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000683 AC: 17 AN: 248800 Hom.: 0 AF XY: 0.0000741 AC XY: 10 AN XY: 134992

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461530 Hom.: 0 Cov.: 31 AF XY: 0.0000935 AC XY: 68 AN XY: 727030

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74370

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000361 AC: 3

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.341G>A (p.R114Q) alteration is located in exon 3 (coding exon 3) of the TTC25 gene. This alteration results from a G to A substitution at nucleotide position 341, causing the arginine (R) at amino acid position 114 to be replaced by a glutamine (Q). 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	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.32	T
REVEL	Benign	0.081
Sift4G	Benign	0.79	T
Polyphen		0.19	B
Vest4		0.20
MVP		0.22
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.29
gMVP		0.12

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

Other links and lift over

dbSNP: rs34520854; hg19: chr17-40091946;