chr5-35641480-A-C

Variant names:

• chr5-35641480-A-C
• rs6897513
• NM_024867.4:c.211A>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.211A>C​(p.Asn71His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 1,613,278 control chromosomes in the GnomAD database, including 268,929 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 0.60 (27983 hom., cov: 32)
  • Exomes 𝑓: 0.57 (240946 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.46
• Publications: 35 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4489497E-6).
• BP6: Variant 5-35641480-A-C is Benign according to our data. Variant chr5-35641480-A-C is described in ClinVar as Benign. ClinVar VariationId is 403471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.717 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	NM_024867.4	MANE Select	c.211A>C	p.Asn71His	missense	Exon 3 of 37	NP_079143.3
	SPEF2	NM_144722.4		c.211A>C	p.Asn71His	missense	Exon 3 of 10	NP_653323.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	ENST00000356031.8	TSL:1 MANE Select	c.211A>C	p.Asn71His	missense	Exon 3 of 37	ENSP00000348314.3
	SPEF2	ENST00000509059.5	TSL:1	c.211A>C	p.Asn71His	missense	Exon 3 of 19	ENSP00000421593.1
	SPEF2	ENST00000282469.10	TSL:1	c.211A>C	p.Asn71His	missense	Exon 3 of 10	ENSP00000282469.6

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91191 AN: 151820 Hom.: 27941 Cov.: 32

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.587

GnomAD2 exomes AF: 0.608 AC: 152691 AN: 251144 AF XY: 0.600

Gnomad AFR exome AF: 0.689

Gnomad AMR exome AF: 0.742

Gnomad ASJ exome AF: 0.565

Gnomad EAS exome AF: 0.739

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.571 AC: 833989 AN: 1461340 Hom.: 240946 Cov.: 51 AF XY: 0.572 AC XY: 415497 AN XY: 726988

African (AFR) AF: 0.689 AC: 23041 AN: 33452

American (AMR) AF: 0.726 AC: 32452 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 14759 AN: 26120

East Asian (EAS) AF: 0.764 AC: 30309 AN: 39684

South Asian (SAS) AF: 0.658 AC: 56730 AN: 86216

European-Finnish (FIN) AF: 0.515 AC: 27479 AN: 53404

Middle Eastern (MID) AF: 0.551 AC: 3175 AN: 5764

European-Non Finnish (NFE) AF: 0.549 AC: 610736 AN: 1111646

Other (OTH) AF: 0.585 AC: 35308 AN: 60380

GnomAD4 genome AF: 0.601 AC: 91297 AN: 151938 Hom.: 27983 Cov.: 32 AF XY: 0.600 AC XY: 44563 AN XY: 74220

African (AFR) AF: 0.683 AC: 28277 AN: 41418

American (AMR) AF: 0.649 AC: 9892 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1987 AN: 3472

East Asian (EAS) AF: 0.737 AC: 3803 AN: 5160

South Asian (SAS) AF: 0.676 AC: 3258 AN: 4822

European-Finnish (FIN) AF: 0.494 AC: 5205 AN: 10542

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 37047 AN: 67974

Other (OTH) AF: 0.585 AC: 1234 AN: 2108

Alfa AF: 0.569 Hom.: 98193

Bravo AF: 0.616

TwinsUK AF: 0.543 AC: 2014

ALSPAC AF: 0.543 AC: 2092

ESP6500AA AF: 0.690 AC: 3041

ESP6500EA AF: 0.547 AC: 4707

ExAC AF: 0.606 AC: 73558

Asia WGS AF: 0.679 AC: 2361 AN: 3478

EpiCase AF: 0.543

EpiControl AF: 0.528

ClinVar

ClinVar submissions as Germline

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	0.036
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.22
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.5	N
PhyloP100		2.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.030
ClinPred		0.0071	T
GERP RS		5.9
Varity_R		0.12
gMVP		0.13
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: rs6897513; hg19: chr5-35641582; COSMIC: COSV56795212;