rs139855000

Variant names:

• chr5-35641517-A-G
• rs139855000
• NM_024867.4:c.248A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-35641517-A-G
• chr5-35641517-A-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.248A>G​(p.His83Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,613,866 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (98 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.14
• Publications: 2 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, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• 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=0.002318412).
• BP6: Variant 5-35641517-A-G is Benign according to our data. Variant chr5-35641517-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0546 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.248A>G	p.His83Arg	missense	Exon 3 of 37	NP_079143.3
	SPEF2	NM_144722.4		c.248A>G	p.His83Arg	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.248A>G	p.His83Arg	missense	Exon 3 of 37	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000509059.5	TSL:1	c.248A>G	p.His83Arg	missense	Exon 3 of 19	ENSP00000421593.1	D6REZ4
	SPEF2	ENST00000282469.10	TSL:1	c.248A>G	p.His83Arg	missense	Exon 3 of 10	ENSP00000282469.6	Q9C093-3

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 605 AN: 152160 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00810 AC: 2036 AN: 251216 AF XY: 0.00625

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00180 AC: 2634 AN: 1461588 Hom.: 98 Cov.: 33 AF XY: 0.00154 AC XY: 1123 AN XY: 727112

African (AFR) AF: 0.000448 AC: 15 AN: 33456

American (AMR) AF: 0.0564 AC: 2520 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111840

Other (OTH) AF: 0.00151 AC: 91 AN: 60382

GnomAD4 genome AF: 0.00401 AC: 611 AN: 152278 Hom.: 15 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74456

African (AFR) AF: 0.000313 AC: 13 AN: 41570

American (AMR) AF: 0.0378 AC: 577 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.000979 Hom.: 6

Bravo AF: 0.00775

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00562 AC: 682

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

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	0.088
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.70
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.077
Sift	Benign	0.81	T
Sift4G	Benign	0.76	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.072
MPC		0.050
ClinPred		0.045	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.23
Mutation Taster		=98/2	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: rs139855000; hg19: chr5-35641619;