11-197345-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.41G>A(p.Arg14His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,594,192 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ODF3 NM_053280.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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=0.0907405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ODF3	NM_053280.5	c.41G>A	p.Arg14His	missense_variant	2/7	ENST00000325113.9
ODF3	NM_001286136.2	c.41G>A	p.Arg14His	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIMAP1A	ENST00000325113.9	c.41G>A	p.Arg14His	missense_variant	2/7	1	NM_053280.5	P1
CIMAP1A	ENST00000525282.1	c.41G>A	p.Arg14His	missense_variant	2/6	1
BET1L	ENST00000410108.5	c.168+8266C>T		intron_variant		3
CIMAP1A	ENST00000531679.1	n.551G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000417 AC: 9 AN: 215784 Hom.: 0 AF XY: 0.0000513 AC XY: 6 AN XY: 117004

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.0000938

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000122

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000213

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1442168 Hom.: 0 Cov.: 32 AF XY: 0.0000224 AC XY: 16 AN XY: 715832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000211

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.0000599

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000726

Gnomad4 OTH exome AF: 0.0000504

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74250

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

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 30, 2023

The c.41G>A (p.R14H) alteration is located in exon 2 (coding exon 1) of the ODF3 gene. This alteration results from a G to A substitution at nucleotide position 41, causing the arginine (R) at amino acid position 14 to be replaced by a histidine (H). 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	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Benign	0.0014
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.0070	B;.;B
Vest4		0.19
MVP		0.13
MPC		0.20
ClinPred		0.044	T
GERP RS		3.6
Varity_R		0.13
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375670921; hg19: chr11-197345; COSMIC: COSV57294908; COSMIC: COSV57294908;