rs138022749

Positions:

• chr5-35771601-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000356031.8(SPEF2):​c.3802-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,586,698 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (142 hom.)
• Consequence: SPEF2 ENST00000356031.8 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006493
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.68

Genes affected

SPEF2 (HGNC:26293): (sperm flagellar 2) Involved in sperm axoneme assembly. Located in sperm flagellum. Implicated in spermatogenic failure 43. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-35771601-G-A is Benign according to our data. Variant chr5-35771601-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403484.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00709 (1079/152194) while in subpopulation SAS AF= 0.0149 (72/4820). AF 95% confidence interval is 0.0122. There are 4 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.3802-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.3802-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024867.4	ENSP00000348314	P2
	ENST00000510433.1	n.173+55245C>T		intron_variant, non_coding_transcript_variant		4
SPEF2	ENST00000440995.6	c.3787-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000412125	A2
SPEF2	ENST00000637569.1	c.3802-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000490886	A2

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1081 AN: 152076 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00785 AC: 1745 AN: 222374 Hom.: 12 AF XY: 0.00846 AC XY: 1025 AN XY: 121136

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.00294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000249

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00691

GnomAD4 exome AF: 0.0124 AC: 17811 AN: 1434504 Hom.: 142 Cov.: 30 AF XY: 0.0125 AC XY: 8938 AN XY: 713310

Gnomad4 AFR exome AF: 0.00195

Gnomad4 AMR exome AF: 0.00339

Gnomad4 ASJ exome AF: 0.0000815

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.00419

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0108

GnomAD4 genome AF: 0.00709 AC: 1079 AN: 152194 Hom.: 4 Cov.: 32 AF XY: 0.00669 AC XY: 498 AN XY: 74418

Gnomad4 AFR AF: 0.00217

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00897 Hom.: 2

Bravo AF: 0.00700

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SPEF2: BP4, BS1, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Candidate PCD gene, but frequency is high -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.25
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.014
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: rs138022749; hg19: chr5-35771703;