5-35654609-C-T

Variant names:

• chr5-35654609-C-T
• rs2270558
• NM_024867.4:c.861C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024867.4(SPEF2):​c.861C>T​(p.Asp287Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,612,478 control chromosomes in the GnomAD database, including 265,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27652 hom., cov: 32)
  • Exomes 𝑓: 0.57 (237529 hom.)
• Consequence: SPEF2 NM_024867.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.121
• Publications: 20 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-35654609-C-T is Benign according to our data. Variant chr5-35654609-C-T is described in ClinVar as [Benign]. Clinvar id is 403473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.121 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.861C>T	p.Asp287Asp	synonymous_variant	Exon 7 of 37	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.861C>T	p.Asp287Asp	synonymous_variant	Exon 7 of 37	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90607 AN: 151856 Hom.: 27610 Cov.: 32

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.646

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.585

GnomAD2 exomes AF: 0.603 AC: 151091 AN: 250526 AF XY: 0.596

Gnomad AFR exome AF: 0.689

Gnomad AMR exome AF: 0.741

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.738

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.539

Gnomad OTH exome AF: 0.572

GnomAD4 exome AF: 0.567 AC: 827403 AN: 1460506 Hom.: 237529 Cov.: 43 AF XY: 0.567 AC XY: 412259 AN XY: 726540

African (AFR) AF: 0.688 AC: 23004 AN: 33422

American (AMR) AF: 0.726 AC: 32332 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 14750 AN: 26106

East Asian (EAS) AF: 0.763 AC: 30283 AN: 39666

South Asian (SAS) AF: 0.658 AC: 56586 AN: 86018

European-Finnish (FIN) AF: 0.497 AC: 26522 AN: 53390

Middle Eastern (MID) AF: 0.549 AC: 3167 AN: 5768

European-Non Finnish (NFE) AF: 0.545 AC: 605664 AN: 1111244

Other (OTH) AF: 0.582 AC: 35095 AN: 60352

GnomAD4 genome AF: 0.597 AC: 90712 AN: 151972 Hom.: 27652 Cov.: 32 AF XY: 0.596 AC XY: 44244 AN XY: 74266

African (AFR) AF: 0.682 AC: 28267 AN: 41430

American (AMR) AF: 0.647 AC: 9880 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1987 AN: 3470

East Asian (EAS) AF: 0.737 AC: 3800 AN: 5154

South Asian (SAS) AF: 0.676 AC: 3254 AN: 4816

European-Finnish (FIN) AF: 0.470 AC: 4958 AN: 10538

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.541 AC: 36738 AN: 67964

Other (OTH) AF: 0.583 AC: 1234 AN: 2116

Alfa AF: 0.556 Hom.: 31413

Bravo AF: 0.613

Asia WGS AF: 0.679 AC: 2361 AN: 3478

EpiCase AF: 0.539

EpiControl AF: 0.524

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.8
DANN	Benign	0.45
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2270558; hg19: chr5-35654711; COSMIC: COSV56799250; COSMIC: COSV56799250;