10-27995057-G-A

Position:

• chr10-27995057-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_018076.5(ODAD2):​c.86C>T​(p.Ala29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,613,014 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: ODAD2 NM_018076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14

Genes affected

ODAD2 (HGNC:25583): (outer dynein arm docking complex subunit 2) The protein encoded by this gene contains ten Armadillo repeat motifs (ARMs) and one HEAT repeat, and is thought to be involved in ciliary and flagellar movement. This protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells. Studies indicate that mutations in this gene cause partial outer dynein arm (ODA) defects in respiratory cilia. The cilia of cells with mutations in this gene displayed either reduced ciliary beat frequency and amplitude, or, complete immotility. Some individuals with primary ciliary dyskensia (PCD) have been shown to have mutations in this gene. PCD is characterized by chronic airway disease and left/right body asymmetry defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

LOC112268060 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051702857).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000184 (28/151916) while in subpopulation SAS AF= 0.00441 (21/4762). AF 95% confidence interval is 0.00295. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ODAD2	NM_018076.5	c.86C>T	p.Ala29Val	missense_variant	2/20	ENST00000305242.10	NP_060546.2
LOC112268060	XR_002957065.1	n.171-11G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ODAD2	ENST00000305242.10	c.86C>T	p.Ala29Val	missense_variant	2/20	1	NM_018076.5	ENSP00000306410	P1
ODAD2	ENST00000673439.1	c.86C>T	p.Ala29Val	missense_variant	2/20			ENSP00000500782	P1
ODAD2	ENST00000486279.2	c.86C>T	p.Ala29Val	missense_variant	3/4	5		ENSP00000473438

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 151798 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00462

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000234 AC: 342 AN: 1461098 Hom.: 3 Cov.: 31 AF XY: 0.000308 AC XY: 224 AN XY: 726770

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00324

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000184 AC: 28 AN: 151916 Hom.: 1 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74236

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00441

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000324 Hom.: 0

ExAC AF: 0.00187 AC: 227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 23 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 29 of the ARMC4 protein (p.Ala29Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ARMC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 474592). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.012
Sift	Benign	0.15	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.0060	B;.
Vest4		0.14
MVP		0.35
MPC		0.18
ClinPred		0.018	T
GERP RS		3.1
Varity_R		0.039
gMVP		0.32

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: rs200574441; hg19: chr10-28283986; COSMIC: COSV100536945; COSMIC: COSV100536945;