11-198571-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053280.5(ODF3):c.520G>A(p.Asp174Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,608,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: ODF3 NM_053280.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.197

Genes affected

ODF3 (HGNC:):

CIMAP1A (HGNC:19905): (ciliary microtubule associated protein 1A) ODF3 is a component of sperm flagella outer dense fibers, which add stiffness, elastic recoil, and protection against shearing forces during sperm movement.[supplied by OMIM, Apr 2004]

BET1L (HGNC:19348): (Bet1 golgi vesicular membrane trafficking protein like) Enables SNAP receptor activity. Involved in regulation of retrograde vesicle-mediated transport, Golgi to ER and retrograde transport, endosome to Golgi. Located in Golgi apparatus and endosome. Implicated in uterine fibroid. Biomarker of endometrial adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14473066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODF3	NM_053280.5	c.520G>A	p.Asp174Asn	missense_variant	5/7	ENST00000325113.9
ODF3	NM_001286136.2	c.520G>A	p.Asp174Asn	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIMAP1A	ENST00000325113.9	c.520G>A	p.Asp174Asn	missense_variant	5/7	1	NM_053280.5	P1
CIMAP1A	ENST00000525282.1	c.520G>A	p.Asp174Asn	missense_variant	5/6	1
BET1L	ENST00000410108.5	c.168+7040C>T		intron_variant		3
CIMAP1A	ENST00000531679.1	n.1363G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151774 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000403 AC: 10 AN: 248280 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1456564 Hom.: 0 Cov.: 33 AF XY: 0.000180 AC XY: 130 AN XY: 724124

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.0000997

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151774 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74150

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.520G>A (p.D174N) alteration is located in exon 5 (coding exon 4) of the ODF3 gene. This alteration results from a G to A substitution at nucleotide position 520, causing the aspartic acid (D) at amino acid position 174 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.94	D;D;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.039
Sift	Uncertain	0.0040	D;D;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.023	B;.;.
Vest4		0.30
MVP		0.23
MPC		0.15
ClinPred		0.14	T
GERP RS		2.3
Varity_R		0.13
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs369827238; hg19: chr11-198571;