chr17-41935662-T-C

Variant names:

• chr17-41935662-T-C
• rs75504508
• NM_031421.5:c.310T>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP3 BP4_Strong BP6 BS1

The NM_031421.5(ODAD4):​c.310T>C​(p.Tyr104His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,613,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ODAD4 NM_031421.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.51

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 -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, PrimateAI [when max_spliceai, MetaRNN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.016992629).
• BP6: Variant 17-41935662-T-C is Benign according to our data. Variant chr17-41935662-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3045956.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00165 (252/152358) while in subpopulation AFR AF= 0.00556 (231/41580). AF 95% confidence interval is 0.00497. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD4	NM_031421.5	c.310T>C	p.Tyr104His	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.310T>C	p.Tyr104His	missense_variant	Exon 3 of 12	1	NM_031421.5	ENSP00000478589.1
ODAD4	ENST00000591658.5	n.310T>C		non_coding_transcript_exon_variant	Exon 3 of 10	5		ENSP00000477931.1
ODAD4	ENST00000585530.1	n.*61+119T>C		intron_variant	Intron 2 of 3	3		ENSP00000479460.1
ODAD4	ENST00000593239.5	n.*61+119T>C		intron_variant	Intron 3 of 5	3		ENSP00000484975.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 253 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.00334

GnomAD3 exomes AF: 0.000407 AC: 101 AN: 248388 Hom.: 0 AF XY: 0.000275 AC XY: 37 AN XY: 134770

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.000174

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: 0.00000888

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461340 Hom.: 0 Cov.: 31 AF XY: 0.000144 AC XY: 105 AN XY: 726920

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74506

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.000915

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: 0.00331

Alfa AF: 0.000249 Hom.: 0

Bravo AF: 0.00178

ESP6500AA AF: 0.00682 AC: 26

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000588 AC: 71

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ODAD4-related disorder Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.14	T
PrimateAI	Pathogenic	0.86	D
REVEL	Uncertain	0.48
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.26
ClinPred		0.19	T
GERP RS		5.8
Varity_R		0.52
gMVP		0.74

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: rs75504508; hg19: chr17-40091915;