5-35641489-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024867.4(SPEF2):c.220G>A(p.Gly74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.05 in 1,613,610 control chromosomes in the GnomAD database, including 2,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. G74G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.054 (253 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1993 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.91

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030751526).
• BP6: Variant 5-35641489-G-A is Benign according to our data. Variant chr5-35641489-G-A is described in ClinVar as [Benign]. Clinvar id is 1270915.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEF2	NM_024867.4	c.220G>A	p.Gly74Ser	missense_variant	3/37	ENST00000356031.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPEF2	ENST00000356031.8	c.220G>A	p.Gly74Ser	missense_variant	3/37	1	NM_024867.4	P2

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8182 AN: 151966 Hom.: 253 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.0961

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0518

Gnomad OTH AF: 0.0437

GnomAD3 exomes AF: 0.0513 AC: 12881 AN: 251194 Hom.: 358 AF XY: 0.0487 AC XY: 6614 AN XY: 135764

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.0547

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.0264

Gnomad FIN exome AF: 0.0947

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0496 AC: 72460 AN: 1461526 Hom.: 1993 Cov.: 33 AF XY: 0.0486 AC XY: 35345 AN XY: 727076

Gnomad4 AFR exome AF: 0.0603

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.0359

Gnomad4 EAS exome AF: 0.00103

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.0920

Gnomad4 NFE exome AF: 0.0514

Gnomad4 OTH exome AF: 0.0441

GnomAD4 genome AF: 0.0539 AC: 8190 AN: 152084 Hom.: 253 Cov.: 32 AF XY: 0.0544 AC XY: 4044 AN XY: 74328

Gnomad4 AFR AF: 0.0627

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0375

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0310

Gnomad4 FIN AF: 0.0961

Gnomad4 NFE AF: 0.0518

Gnomad4 OTH AF: 0.0437

Alfa AF: 0.0458 Hom.: 95

Bravo AF: 0.0502

TwinsUK AF: 0.0504 AC: 187

ALSPAC AF: 0.0535 AC: 206

ESP6500AA AF: 0.0667 AC: 294

ESP6500EA AF: 0.0519 AC: 446

ExAC AF: 0.0530 AC: 6440

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0481

EpiControl AF: 0.0446

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
MetaRNN	Benign	0.0031	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M;.;.;M;.;M
MutationTaster	Benign	0.57	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N;D;.;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.22	T;T;.;T;T;T
Sift4G	Benign	0.10	T;T;.;D;D;D
Polyphen		0.57	P;P;.;D;.;.
Vest4		0.55
MPC		0.23
ClinPred		0.046	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.42

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

Other links and lift over

dbSNP: rs34307272; hg19: chr5-35641591;