rs139580877

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024867.4(SPEF2):c.1262G>A(p.Arg421His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,612,356 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0072 ( 2 hom., cov: 33)

Exomes 𝑓: 0.012 ( 137 hom. )

Consequence

SPEF2
NM_024867.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.37

Variant links:

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]

SPEF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0092085).

BP6

Variant 5-35667166-G-A is Benign according to our data. Variant chr5-35667166-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403482.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00724 (1102/152298) while in subpopulation SAS AF= 0.0141 (68/4826). AF 95% confidence interval is 0.0114. There are 2 homozygotes in gnomad4. There are 517 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEF2	NM_024867.4 linkuse as main transcript	c.1262G>A	p.Arg421His	missense_variant	9/37	ENST00000356031.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPEF2	ENST00000356031.8 linkuse as main transcript	c.1262G>A	p.Arg421His	missense_variant	9/37	1	NM_024867.4	P2	Q9C093-1

Frequencies

GnomAD3 genomes

AF:

0.00725

AC:

1103

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0143

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00768

AC:

1917

AN:

249766

Hom.:

AF XY:

0.00838

AC XY:

1131

AN XY:

134902

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.00296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00136

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.00361

Gnomad NFE exome

AF:

0.0110

Gnomad OTH exome

AF:

0.00691

GnomAD4 exome

AF:

0.0121

AC:

17631

AN:

1460058

Hom.:

137

Cov.:

AF XY:

0.0122

AC XY:

8847

AN XY:

726176

show subpopulations

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.00350

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00172

Gnomad4 SAS exome

AF:

0.0132

Gnomad4 FIN exome

AF:

0.00414

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00724

AC:

1102

AN:

152298

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

517

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00219

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00348

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00932

Hom.:

Bravo

AF:

0.00724

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0136

AC:

117

ExAC

AF:

0.00777

AC:

943

Asia WGS

AF:

0.00433

AC:

AN:

3476

EpiCase

AF:

0.0107

EpiControl

AF:

0.0110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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 -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

SPEF2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.039

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

T;T;T;T;T

MetaRNN

Benign

0.0092

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;.;.;M;M

MutationTaster

Benign

0.82

D;D;D;D

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-4.0

D;D;.;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0080

D;D;.;D;D

Sift4G

Uncertain

0.0070

D;D;.;D;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.18

MVP

0.49

MPC

0.056

ClinPred

0.044

GERP RS

2.0

Varity_R

0.083

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over