chr5-35670201-G-A

Variant names:

• chr5-35670201-G-A
• rs34708521
• NM_024867.4:c.1498G>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.1498G>A​(p.Asp500Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0753 in 1,609,122 control chromosomes in the GnomAD database, including 6,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (795 hom., cov: 32)
  • Exomes 𝑓: 0.074 (5977 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.16
• Publications: 22 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=0.0014680028).
• BP6: Variant 5-35670201-G-A is Benign according to our data. Variant chr5-35670201-G-A is described in ClinVar as Benign. ClinVar VariationId is 403474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.308 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.1498G>A	p.Asp500Asn	missense	Exon 10 of 37	NP_079143.3
	SPEF2	NM_144722.4		c.1498G>A	p.Asp500Asn	missense	Exon 10 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.1498G>A	p.Asp500Asn	missense	Exon 10 of 37	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000509059.5	TSL:1	c.1498G>A	p.Asp500Asn	missense	Exon 10 of 19	ENSP00000421593.1	D6REZ4
	SPEF2	ENST00000282469.10	TSL:1	c.1498G>A	p.Asp500Asn	missense	Exon 10 of 10	ENSP00000282469.6	Q9C093-3

Frequencies

GnomAD3 genomes AF: 0.0850 AC: 12905 AN: 151856 Hom.: 793 Cov.: 32

Gnomad AFR AF: 0.0970

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.0885

GnomAD2 exomes AF: 0.100 AC: 24921 AN: 248672 AF XY: 0.0951

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.0500

Gnomad EAS exome AF: 0.329

Gnomad FIN exome AF: 0.0643

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0750

GnomAD4 exome AF: 0.0743 AC: 108213 AN: 1457148 Hom.: 5977 Cov.: 31 AF XY: 0.0736 AC XY: 53333 AN XY: 724850

African (AFR) AF: 0.100 AC: 3339 AN: 33306

American (AMR) AF: 0.162 AC: 7178 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.0480 AC: 1246 AN: 25980

East Asian (EAS) AF: 0.337 AC: 13298 AN: 39480

South Asian (SAS) AF: 0.0888 AC: 7600 AN: 85582

European-Finnish (FIN) AF: 0.0656 AC: 3498 AN: 53354

Middle Eastern (MID) AF: 0.0440 AC: 253 AN: 5746

European-Non Finnish (NFE) AF: 0.0602 AC: 66829 AN: 1109196

Other (OTH) AF: 0.0826 AC: 4972 AN: 60218

GnomAD4 genome AF: 0.0850 AC: 12914 AN: 151974 Hom.: 795 Cov.: 32 AF XY: 0.0867 AC XY: 6438 AN XY: 74256

African (AFR) AF: 0.0970 AC: 4025 AN: 41496

American (AMR) AF: 0.123 AC: 1872 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.321 AC: 1656 AN: 5164

South Asian (SAS) AF: 0.101 AC: 488 AN: 4818

European-Finnish (FIN) AF: 0.0596 AC: 631 AN: 10584

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0568 AC: 3854 AN: 67870

Other (OTH) AF: 0.0866 AC: 183 AN: 2112

Alfa AF: 0.0720 Hom.: 2130

Bravo AF: 0.0924

TwinsUK AF: 0.0653 AC: 242

ALSPAC AF: 0.0584 AC: 225

ESP6500AA AF: 0.0994 AC: 438

ESP6500EA AF: 0.0528 AC: 454

ExAC AF: 0.0966 AC: 11729

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.2
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Benign	0.26	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.18
ClinPred		0.014	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.27
Mutation Taster		=89/11	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: rs34708521; hg19: chr5-35670303; COSMIC: COSV107289422;