chr5-35709082-G-C

Position:

• chr5-35709082-G-C

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.2800G>C​(p.Ala934Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,613,346 control chromosomes in the GnomAD database, including 487,090 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43326 hom., cov: 31)
  • Exomes 𝑓: 0.78 (443764 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.47

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2953827E-5).
• BP6: Variant 5-35709082-G-C is Benign according to our data. Variant chr5-35709082-G-C is described in ClinVar as [Benign]. Clinvar id is 403479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.2800G>C	p.Ala934Pro	missense_variant	19/37	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.2800G>C	p.Ala934Pro	missense_variant	19/37	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114257 AN: 151964 Hom.: 43311 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.770

GnomAD3 exomes AF: 0.755 AC: 187832 AN: 248832 Hom.: 71451 AF XY: 0.758 AC XY: 102334 AN XY: 134998

Gnomad AFR exome AF: 0.660

Gnomad AMR exome AF: 0.681

Gnomad ASJ exome AF: 0.804

Gnomad EAS exome AF: 0.776

Gnomad SAS exome AF: 0.697

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.794

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.778 AC: 1137128 AN: 1461264 Hom.: 443764 Cov.: 50 AF XY: 0.777 AC XY: 564449 AN XY: 726882

Gnomad4 AFR exome AF: 0.663

Gnomad4 AMR exome AF: 0.692

Gnomad4 ASJ exome AF: 0.801

Gnomad4 EAS exome AF: 0.799

Gnomad4 SAS exome AF: 0.699

Gnomad4 FIN exome AF: 0.769

Gnomad4 NFE exome AF: 0.790

Gnomad4 OTH exome AF: 0.775

GnomAD4 genome AF: 0.752 AC: 114321 AN: 152082 Hom.: 43326 Cov.: 31 AF XY: 0.752 AC XY: 55934 AN XY: 74336

Gnomad4 AFR AF: 0.664

Gnomad4 AMR AF: 0.774

Gnomad4 ASJ AF: 0.787

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.685

Gnomad4 FIN AF: 0.782

Gnomad4 NFE AF: 0.794

Gnomad4 OTH AF: 0.771

Alfa AF: 0.786 Hom.: 15329

Bravo AF: 0.744

TwinsUK AF: 0.791 AC: 2932

ALSPAC AF: 0.790 AC: 3045

ESP6500AA AF: 0.672 AC: 2496

ESP6500EA AF: 0.794 AC: 6506

ExAC AF: 0.755 AC: 91235

Asia WGS AF: 0.713 AC: 2479 AN: 3476

EpiCase AF: 0.800

EpiControl AF: 0.800

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

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 -

Spermatogenic failure 43 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.030
DANN	Benign	0.48
DEOGEN2	Benign	0.0016	.;T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.32	T;T;T;T
MetaRNN	Benign	0.000023	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	.;.;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.23	N;.;N;N
REVEL	Benign	0.020
Sift	Benign	0.54	T;.;T;T
Sift4G	Benign	0.43	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.043
MPC		0.034
ClinPred		0.00030	T
GERP RS		-2.1
Varity_R		0.044
gMVP		0.17

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: rs13170390; hg19: chr5-35709184; COSMIC: COSV61545824; COSMIC: COSV61545824;