Genetic Variant SPEF2:p.Ile193Met (chr5-35644519-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024867.4(SPEF2):c.579T>G(p.Ile193Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I193I) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPEF2
NM_024867.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

19 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02896005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEF2	NM_024867.4 link	c.579T>G	p.Ile193Met	missense_variant	Exon 4 of 37	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8 link	c.579T>G	p.Ile193Met	missense_variant	Exon 4 of 37	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1440114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715768

African (AFR)

AF:

0.00

AC:

AN:

31940

American (AMR)

AF:

0.00

AC:

AN:

39130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25020

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.00

AC:

AN:

81922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104812

Other (OTH)

AF:

0.00

AC:

AN:

59302

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.042

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.011

.;.;T;T;.

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.58

T;T;T;T;T

M_CAP

Benign

0.0060

MetaRNN

Benign

0.029

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.;.;L;L

PhyloP100

-1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.68

N;N;.;N;N

REVEL

Benign

0.020

Sift

Benign

0.15

T;T;.;T;T

Sift4G

Benign

0.20

T;T;.;T;T

Polyphen

0.017

B;B;.;B;.

Vest4

0.087

MutPred

0.28

Loss of catalytic residue at L198 (P = 0.0522);Loss of catalytic residue at L198 (P = 0.0522);Loss of catalytic residue at L198 (P = 0.0522);Loss of catalytic residue at L198 (P = 0.0522);Loss of catalytic residue at L198 (P = 0.0522);

MVP

0.055

MPC

0.030

ClinPred

0.086

GERP RS

-9.6

Varity_R

0.062

gMVP

0.073

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over