NM_024867.4:c.2711C>T

Variant names:

• chr5-35708993-C-T
• rs13170082
• NM_024867.4:c.2711C>T

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.2711C>T​(p.Ala904Val) 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 1,612,208 control chromosomes in the GnomAD database, including 486,889 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43293 hom., cov: 30)
  • Exomes 𝑓: 0.78 (443596 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0590
• Publications: 27 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):

• primary ciliary dyskinesia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• spermatogenic failure 43

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=3.6450936E-5).
• BP6: Variant 5-35708993-C-T is Benign according to our data. Variant chr5-35708993-C-T is described in ClinVar as Benign. ClinVar VariationId is 403478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024867.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	NM_024867.4	MANE Select	c.2711C>T	p.Ala904Val	missense	Exon 19 of 37	NP_079143.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	ENST00000356031.8	TSL:1 MANE Select	c.2711C>T	p.Ala904Val	missense	Exon 19 of 37	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000509059.5	TSL:1	c.2696C>T	p.Ala899Val	missense	Exon 19 of 19	ENSP00000421593.1	D6REZ4
	SPEF2	ENST00000637569.1	TSL:5	c.2711C>T	p.Ala904Val	missense	Exon 19 of 35	ENSP00000490886.1	A0A1B0GWD8

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114159 AN: 151828 Hom.: 43278 Cov.: 30

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.827

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.788

Gnomad EAS AF: 0.781

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

GnomAD2 exomes AF: 0.755 AC: 187398 AN: 248160 AF XY: 0.758

Gnomad AFR exome AF: 0.660

Gnomad AMR exome AF: 0.681

Gnomad ASJ exome AF: 0.805

Gnomad EAS exome AF: 0.776

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.794

Gnomad OTH exome AF: 0.773

GnomAD4 exome AF: 0.778 AC: 1136506 AN: 1460262 Hom.: 443596 Cov.: 46 AF XY: 0.777 AC XY: 564161 AN XY: 726406

African (AFR) AF: 0.663 AC: 22122 AN: 33360

American (AMR) AF: 0.692 AC: 30743 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 20925 AN: 26112

East Asian (EAS) AF: 0.799 AC: 31710 AN: 39674

South Asian (SAS) AF: 0.700 AC: 60065 AN: 85858

European-Finnish (FIN) AF: 0.769 AC: 41033 AN: 53364

Middle Eastern (MID) AF: 0.824 AC: 4745 AN: 5760

European-Non Finnish (NFE) AF: 0.790 AC: 878378 AN: 1111368

Other (OTH) AF: 0.775 AC: 46785 AN: 60334

GnomAD4 genome AF: 0.752 AC: 114223 AN: 151946 Hom.: 43293 Cov.: 30 AF XY: 0.753 AC XY: 55878 AN XY: 74250

African (AFR) AF: 0.664 AC: 27529 AN: 41446

American (AMR) AF: 0.774 AC: 11820 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 2733 AN: 3470

East Asian (EAS) AF: 0.781 AC: 4018 AN: 5146

South Asian (SAS) AF: 0.685 AC: 3298 AN: 4812

European-Finnish (FIN) AF: 0.782 AC: 8244 AN: 10544

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 53963 AN: 67944

Other (OTH) AF: 0.771 AC: 1623 AN: 2106

Alfa AF: 0.776 Hom.: 20144

Bravo AF: 0.744

TwinsUK AF: 0.791 AC: 2932

ALSPAC AF: 0.791 AC: 3047

ESP6500AA AF: 0.672 AC: 2520

ESP6500EA AF: 0.795 AC: 6530

ExAC AF: 0.755 AC: 91224

Asia WGS AF: 0.714 AC: 2483 AN: 3478

EpiCase AF: 0.800

EpiControl AF: 0.800

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spermatogenic failure 43 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.4
DANN	Benign	0.78
DEOGEN2	Benign	0.0059	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.000036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.059
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.10
Sift	Benign	0.57	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.047
MPC		0.029
ClinPred		0.0053	T
GERP RS		-2.8
Varity_R		0.029
gMVP		0.23
Mutation Taster		=99/1	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: rs13170082; hg19: chr5-35709095; COSMIC: COSV61548352; COSMIC: COSV61548352;