rs34708521

chr5-35670201-G-Achr5-35670201-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024867.4(SPEF2):c.1498G>A(p.Asp500Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0753 in 1,609,122 control chromosomes in the GnomAD database, including 6,772 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.

• Frequency:
  • Genomes: 𝑓 0.085 (795 hom., cov: 32)
  • Exomes 𝑓: 0.074 (5977 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014680028).
• BP6: Variant 5-35670201-G-A is Benign according to our data. Variant chr5-35670201-G-A is described in ClinVar as [Benign]. Clinvar id is 403474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPEF2	NM_024867.4	c.1498G>A	p.Asp500Asn	missense_variant	10/37	ENST00000356031.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPEF2	ENST00000356031.8	c.1498G>A	p.Asp500Asn	missense_variant	10/37	1	NM_024867.4	P2

Frequencies

GnomAD3 genomes AF: 0.0850 AC: 12905 AN: 151856 Hom.: 793 Cov.: 32

Gnomad AFR AF: 0.0970

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0885

GnomAD3 exomes AF: 0.100 AC: 24921 AN: 248672 Hom.: 2010 AF XY: 0.0951 AC XY: 12791 AN XY: 134436

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.329

Gnomad SAS exome AF: 0.0909

Gnomad FIN exome AF: 0.0643

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0750

GnomAD4 exome AF: 0.0743 AC: 108213 AN: 1457148 Hom.: 5977 Cov.: 31 AF XY: 0.0736 AC XY: 53333 AN XY: 724850

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.0480

Gnomad4 EAS exome AF: 0.337

Gnomad4 SAS exome AF: 0.0888

Gnomad4 FIN exome AF: 0.0656

Gnomad4 NFE exome AF: 0.0602

Gnomad4 OTH exome AF: 0.0826

GnomAD4 genome AF: 0.0850 AC: 12914 AN: 151974 Hom.: 795 Cov.: 32 AF XY: 0.0867 AC XY: 6438 AN XY: 74256

Gnomad4 AFR AF: 0.0970

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.321

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0596

Gnomad4 NFE AF: 0.0568

Gnomad4 OTH AF: 0.0866

Alfa AF: 0.0696 Hom.: 920

Bravo AF: 0.0924

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0584 AC: 225

ESP6500AA AF: 0.0994 AC: 438

ESP6500EA AF: 0.0528 AC: 454

ExAC AF: 0.0966 AC: 11729

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, 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: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M;.;.;M;M
MutationTaster	Benign	0.038	P;P;P;P
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D;N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.26	T;T;.;T;T
Sift4G	Benign	0.40	T;T;.;T;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.11
MPC		0.18
ClinPred		0.014	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.27

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: rs34708521; hg19: chr5-35670303;