rs7710284

Positions:

• chr5-35692673-T-A
• chr5-35692673-T-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.1848T>A​(p.Asn616Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,792 control chromosomes in the GnomAD database, including 33,137 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (8222 hom., cov: 32)
  • Exomes 𝑓: 0.16 (24915 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.395

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=1.6021313E-5).
• BP6: Variant 5-35692673-T-A is Benign according to our data. Variant chr5-35692673-T-A is described in ClinVar as [Benign]. Clinvar id is 403475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.1848T>A	p.Asn616Lys	missense_variant	12/37	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.1848T>A	p.Asn616Lys	missense_variant	12/37	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41450 AN: 151826 Hom.: 8182 Cov.: 32

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.0703

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.219 AC: 54506 AN: 248760 Hom.: 7746 AF XY: 0.207 AC XY: 27968 AN XY: 135008

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.399

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.163 AC: 237833 AN: 1460848 Hom.: 24915 Cov.: 32 AF XY: 0.162 AC XY: 117633 AN XY: 726778

Gnomad4 AFR exome AF: 0.566

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.406

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.273 AC: 41551 AN: 151944 Hom.: 8222 Cov.: 32 AF XY: 0.275 AC XY: 20406 AN XY: 74238

Gnomad4 AFR AF: 0.551

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.132

Gnomad4 OTH AF: 0.233

Alfa AF: 0.175 Hom.: 1037

Bravo AF: 0.291

TwinsUK AF: 0.131 AC: 486

ALSPAC AF: 0.130 AC: 502

ESP6500AA AF: 0.549 AC: 2023

ESP6500EA AF: 0.131 AC: 1069

ExAC AF: 0.222 AC: 26795

Asia WGS AF: 0.306 AC: 1066 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.124

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.068
DANN	Benign	0.55
DEOGEN2	Benign	0.0025	.;T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.11	T;T;T;T
MetaRNN	Benign	0.000016	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.90	.;.;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.32	N;.;N;N
REVEL	Benign	0.0010
Sift	Benign	0.89	T;.;T;T
Sift4G	Benign	0.87	T;.;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.016
MutPred		0.22		Gain of ubiquitination at N616 (P = 0.0014);Gain of ubiquitination at N616 (P = 0.0014);Gain of ubiquitination at N616 (P = 0.0014);Gain of ubiquitination at N616 (P = 0.0014);
MPC		0.032
ClinPred		0.0042	T
GERP RS		-3.6
Varity_R		0.034
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: rs7710284; hg19: chr5-35692775; COSMIC: COSV61548485;