rs201977207

chr19-11426909-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_145045.5(ODAD3):c.576G>T(p.Met192Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,609,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ODAD3 NM_145045.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.0850

Genes affected

ODAD3 (HGNC:28303): (outer dynein arm docking complex subunit 3) This gene encodes a protein containing coiled-coil domains. The encoded protein functions in outer dynein arm assembly and is required for motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03209251).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000124 (181/1457578) while in subpopulation AMR AF= 0.000717 (32/44614). AF 95% confidence interval is 0.000522. There are 0 homozygotes in gnomad4_exome. There are 99 alleles in male gnomad4_exome 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODAD3	NM_145045.5	c.576G>T	p.Met192Ile	missense_variant	4/13	ENST00000356392.9
ODAD3	NM_001302453.1	c.414G>T	p.Met138Ile	missense_variant	4/13
ODAD3	NM_001302454.2	c.498G>T	p.Met166Ile	missense_variant	3/11
ODAD3	XM_017026241.2	c.576G>T	p.Met192Ile	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ODAD3	ENST00000356392.9	c.576G>T	p.Met192Ile	missense_variant	4/13	1	NM_145045.5	P2
ODAD3	ENST00000591179.5	c.498G>T	p.Met166Ile	missense_variant	3/11	1		A2
ODAD3	ENST00000586836.5	c.3G>T	p.Met1?	start_lost	4/13	2		A2
ODAD3	ENST00000591345.5	c.*495G>T		3_prime_UTR_variant, NMD_transcript_variant	5/14	5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 54 AN: 246490 Hom.: 0 AF XY: 0.000231 AC XY: 31 AN XY: 133936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000640

Gnomad ASJ exome AF: 0.000602

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000152

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1457578 Hom.: 0 Cov.: 33 AF XY: 0.000137 AC XY: 99 AN XY: 724718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000717

Gnomad4 ASJ exome AF: 0.000614

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000982

Gnomad4 OTH exome AF: 0.000299

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000240 AC: 29

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.576G>T (p.M192I) alteration is located in exon 4 (coding exon 4) of the CCDC151 gene. This alteration results from a G to T substitution at nucleotide position 576, causing the methionine (M) at amino acid position 192 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 30 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 192 of the CCDC151 protein (p.Met192Ile). This variant is present in population databases (rs201977207, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CCDC151-related conditions. ClinVar contains an entry for this variant (Variation ID: 477985). 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 isoleucine 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	0.30
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	3.2
Dann	Benign	0.60
DEOGEN2	Benign	0.0031	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.63	T;T;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.79	N;.;.
MutationTaster	Benign	0.99	D;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.62	N;.;.
REVEL	Benign	0.16
Sift	Benign	0.43	T;.;.
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.069
MutPred		0.28		Loss of MoRF binding (P = 0.0865);.;.;
MVP		0.60
MPC		0.49
ClinPred		0.021	T
GERP RS		-2.0
Varity_R		0.042
gMVP		0.13

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: rs201977207; hg19: chr19-11537729;