5-35753613-T-C

Variant names:

• chr5-35753613-T-C
• rs11957963
• NM_024867.4:c.3331-11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024867.4(SPEF2):​c.3331-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,613,546 control chromosomes in the GnomAD database, including 325,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (24742 hom., cov: 32)
  • Exomes 𝑓: 0.64 (300660 hom.)
• Consequence: SPEF2 NM_024867.4 intron
• Scores: Splicing: ADA: 0.00007130
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.983
• Publications: 10 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

ENSG00000248969 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-35753613-T-C is Benign according to our data. Variant chr5-35753613-T-C is described in ClinVar as Benign. ClinVar VariationId is 403481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.3331-11T>C		intron_variant	Intron 23 of 36	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.3331-11T>C		intron_variant	Intron 23 of 36	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82160 AN: 151970 Hom.: 24744 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.582

GnomAD2 exomes AF: 0.598 AC: 149039 AN: 249180 AF XY: 0.606

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.562

Gnomad ASJ exome AF: 0.630

Gnomad EAS exome AF: 0.657

Gnomad FIN exome AF: 0.580

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.637 AC: 931048 AN: 1461458 Hom.: 300660 Cov.: 51 AF XY: 0.637 AC XY: 462828 AN XY: 727056

African (AFR) AF: 0.242 AC: 8100 AN: 33476

American (AMR) AF: 0.568 AC: 25379 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 16465 AN: 26132

East Asian (EAS) AF: 0.688 AC: 27293 AN: 39690

South Asian (SAS) AF: 0.566 AC: 48836 AN: 86238

European-Finnish (FIN) AF: 0.579 AC: 30927 AN: 53408

Middle Eastern (MID) AF: 0.662 AC: 3722 AN: 5620

European-Non Finnish (NFE) AF: 0.659 AC: 732673 AN: 1111810

Other (OTH) AF: 0.624 AC: 37653 AN: 60364

GnomAD4 genome AF: 0.540 AC: 82151 AN: 152088 Hom.: 24742 Cov.: 32 AF XY: 0.541 AC XY: 40219 AN XY: 74338

African (AFR) AF: 0.257 AC: 10662 AN: 41488

American (AMR) AF: 0.632 AC: 9651 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3468

East Asian (EAS) AF: 0.671 AC: 3465 AN: 5164

South Asian (SAS) AF: 0.555 AC: 2669 AN: 4812

European-Finnish (FIN) AF: 0.594 AC: 6272 AN: 10562

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.664 AC: 45120 AN: 67998

Other (OTH) AF: 0.584 AC: 1233 AN: 2112

Alfa AF: 0.587 Hom.: 5893

Bravo AF: 0.527

Asia WGS AF: 0.589 AC: 2052 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.83
CADD	Benign	3.9
DANN	Benign	0.44
PhyloP100		0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.0020
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: rs11957963; hg19: chr5-35753715; COSMIC: COSV61552428;