19-48297459-CGCGGCGGCG-CGCGGCGGCGGCG

Variant names:

• chr19-48297459-C-CGCG
• rs761748771
• NM_001364171.2:c.1638_1640dupCGC

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001364171.2(ODAD1):​c.1638_1640dupCGC​(p.Ala547dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,601,126 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (2 hom.)
• Consequence: ODAD1 NM_001364171.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.84

Genes affected

ODAD1 (HGNC:26560): (outer dynein arm docking complex subunit 1) This gene encodes a coiled-coil domain-containing protein that is a component of the outer dynein arm docking complex in cilia cells. Mutations in this gene may cause primary ciliary dyskinesia 20. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001364171.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-48297459-C-CGCG is Benign according to our data. Variant chr19-48297459-C-CGCG is described in ClinVar as [Likely_benign]. Clinvar id is 406184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000453 (656/1448892) while in subpopulation SAS AF= 0.00232 (199/85804). AF 95% confidence interval is 0.00206. There are 2 homozygotes in gnomad4_exome. There are 383 alleles in male gnomad4_exome subpopulation. Median coverage is 62. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ODAD1	NM_001364171.2	c.1638_1640dupCGC	p.Ala547dup	disruptive_inframe_insertion	Exon 16 of 16	ENST00000674294.1	NP_001351100.1
ODAD1	NM_144577.4	c.1527_1529dupCGC	p.Ala510dup	disruptive_inframe_insertion	Exon 14 of 14		NP_653178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ODAD1	ENST00000674294.1	c.1638_1640dupCGC	p.Ala547dup	disruptive_inframe_insertion	Exon 16 of 16		NM_001364171.2	ENSP00000501363.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000582 AC: 135 AN: 231928 Hom.: 0 AF XY: 0.000675 AC XY: 86 AN XY: 127322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000911

Gnomad ASJ exome AF: 0.00390

Gnomad EAS exome AF: 0.000282

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.000703

GnomAD4 exome AF: 0.000453 AC: 656 AN: 1448892 Hom.: 2 Cov.: 62 AF XY: 0.000531 AC XY: 383 AN XY: 720874

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00471

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.0000218

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000634

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74420

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.000434

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ODAD1-related disorder Benign:1

Oct 20, 2022

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs761748771; hg19: chr19-48800716;