rs139580877

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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:2B:1

Conservation

PhyloP100: 3.37

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

spermatogenic failure 43
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SPEF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 403482.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEF2	NM_024867.4 link	c.1262G>A	p.Arg421His	missense_variant	Exon 9 of 37	ENST00000356031.8	NP_079143.3	Q9C093-1A0A140VKD0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8 link	c.1262G>A	p.Arg421His	missense_variant	Exon 9 of 37	1	NM_024867.4	ENSP00000348314.3		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

GnomAD2 exomes

AF:

0.00768

AC:

1917

AN:

249766

AF XY:

0.00838

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 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

African (AFR)

AF:

0.00186

AC:

AN:

33404

American (AMR)

AF:

0.00350

AC:

156

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26086

East Asian (EAS)

AF:

0.00172

AC:

AN:

39608

South Asian (SAS)

AF:

0.0132

AC:

1132

AN:

85808

European-Finnish (FIN)

AF:

0.00414

AC:

221

AN:

53386

Middle Eastern (MID)

AF:

0.00579

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0138

AC:

15316

AN:

1111236

Other (OTH)

AF:

0.0106

AC:

639

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

916

1832

2749

3665

4581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00724

AC:

1102

AN:

152298

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

517

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41572

American (AMR)

AF:

0.00425

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00135

AC:

AN:

5186

South Asian (SAS)

AF:

0.0141

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

813

AN:

68020

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPEF2: BP4, BS1, BS2 -

not specified

Uncertain:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;.;T;D;.

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

PhyloP100

3.4

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

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over