chr5-35641489-G-A

Variant names:

• chr5-35641489-G-A
• rs34307272
• NM_024867.4:c.220G>A

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.220G>A​(p.Gly74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.05 in 1,613,610 control chromosomes in the GnomAD database, including 2,246 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (253 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1993 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.91
• Publications: 9 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030751526).
• BP6: Variant 5-35641489-G-A is Benign according to our data. Variant chr5-35641489-G-A is described in ClinVar as Benign. ClinVar VariationId is 1270915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0606 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.220G>A	p.Gly74Ser	missense	Exon 3 of 37	NP_079143.3
	SPEF2	NM_144722.4		c.220G>A	p.Gly74Ser	missense	Exon 3 of 10	NP_653323.1	Q9C093-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	ENST00000356031.8	TSL:1 MANE Select	c.220G>A	p.Gly74Ser	missense	Exon 3 of 37	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000509059.5	TSL:1	c.220G>A	p.Gly74Ser	missense	Exon 3 of 19	ENSP00000421593.1	D6REZ4
	SPEF2	ENST00000282469.10	TSL:1	c.220G>A	p.Gly74Ser	missense	Exon 3 of 10	ENSP00000282469.6	Q9C093-3

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8182 AN: 151966 Hom.: 253 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0375

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.0961

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0518

Gnomad OTH AF: 0.0437

GnomAD2 exomes AF: 0.0513 AC: 12881 AN: 251194 AF XY: 0.0487

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.0547

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.00228

Gnomad FIN exome AF: 0.0947

Gnomad NFE exome AF: 0.0559

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0496 AC: 72460 AN: 1461526 Hom.: 1993 Cov.: 33 AF XY: 0.0486 AC XY: 35345 AN XY: 727076

African (AFR) AF: 0.0603 AC: 2018 AN: 33458

American (AMR) AF: 0.0548 AC: 2450 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 938 AN: 26116

East Asian (EAS) AF: 0.00103 AC: 41 AN: 39688

South Asian (SAS) AF: 0.0251 AC: 2167 AN: 86246

European-Finnish (FIN) AF: 0.0920 AC: 4912 AN: 53406

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5766

European-Non Finnish (NFE) AF: 0.0514 AC: 57141 AN: 1111788

Other (OTH) AF: 0.0441 AC: 2660 AN: 60380

GnomAD4 genome AF: 0.0539 AC: 8190 AN: 152084 Hom.: 253 Cov.: 32 AF XY: 0.0544 AC XY: 4044 AN XY: 74328

African (AFR) AF: 0.0627 AC: 2599 AN: 41480

American (AMR) AF: 0.0423 AC: 646 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0375 AC: 130 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5172

South Asian (SAS) AF: 0.0310 AC: 149 AN: 4812

European-Finnish (FIN) AF: 0.0961 AC: 1016 AN: 10572

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0518 AC: 3522 AN: 67994

Other (OTH) AF: 0.0437 AC: 92 AN: 2106

Alfa AF: 0.0501 Hom.: 420

Bravo AF: 0.0502

TwinsUK AF: 0.0504 AC: 187

ALSPAC AF: 0.0535 AC: 206

ESP6500AA AF: 0.0667 AC: 294

ESP6500EA AF: 0.0519 AC: 446

ExAC AF: 0.0530 AC: 6440

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0481

EpiControl AF: 0.0446

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.097
Sift	Benign	0.22	T
Sift4G	Benign	0.10	T
Polyphen		0.57	P
Vest4		0.55
MPC		0.23
ClinPred		0.046	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.42
Mutation Taster		=85/15	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: rs34307272; hg19: chr5-35641591; COSMIC: COSV106356581;