17-8345346-C-G

Variant names:

• chr17-8345346-C-G
• rs369506738
• NM_153007.5:c.458C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_153007.5(ODF4):​c.458C>G​(p.Thr153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T153I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ODF4 NM_153007.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.457
• Publications: 0 publications found

Genes affected

ODF4 (HGNC:19056): (outer dense fiber of sperm tails 4) This gene encodes a protein that is localized in the outer dense fibers of the tails of mature sperm. This protein is thought to have some important role in the sperm tail. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ODF4 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153007.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODF4	NM_153007.5	MANE Select	c.458C>G	p.Thr153Ser	missense	Exon 2 of 3	NP_694552.2	Q2M2E3
	ODF4	NM_001319953.2		c.113C>G	p.Thr38Ser	missense	Exon 2 of 3	NP_001306882.1	C3TX97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ODF4	ENST00000328248.7	TSL:1 MANE Select	c.458C>G	p.Thr153Ser	missense	Exon 2 of 3	ENSP00000331086.2	Q2M2E3
	ODF4	ENST00000584943.1	TSL:1	c.113C>G	p.Thr38Ser	missense	Exon 2 of 3	ENSP00000461942.1	C3TX97
	ODF4	ENST00000636237.1	TSL:5	n.*124C>G		non_coding_transcript_exon	Exon 3 of 4	ENSP00000490099.1	A0A1B0GUG5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461248 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726964

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111562

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.0
DANN	Benign	0.27
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.46
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.037
Sift	Benign	0.71	T
Sift4G	Benign	0.16	T
Polyphen		0.046	B
Vest4		0.16
MutPred		0.28		Gain of disorder (P = 0.0433)
MVP		0.014
MPC		0.20
ClinPred		0.031	T
GERP RS		-5.6
Varity_R		0.046
gMVP		0.061

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 1

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

Other links and lift over

dbSNP: rs369506738; hg19: chr17-8248664;