rs138022749

Variant names:

• chr5-35771601-G-A
• rs138022749
• NM_024867.4:c.3802-8G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024867.4(SPEF2):​c.3802-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,586,698 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (142 hom.)
• Consequence: SPEF2 NM_024867.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006493
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.68
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-35771601-G-A is Benign according to our data. Variant chr5-35771601-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403484.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00709 (1079/152194) while in subpopulation SAS AF = 0.0149 (72/4820). AF 95% confidence interval is 0.0122. There are 4 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.3802-8G>A		splice_region intron	N/A	NP_079143.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	ENST00000356031.8	TSL:1 MANE Select	c.3802-8G>A		splice_region intron	N/A	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000637569.1	TSL:5	c.3802-8G>A		splice_region intron	N/A	ENSP00000490886.1	A0A1B0GWD8
	SPEF2	ENST00000440995.6	TSL:5	c.3787-8G>A		splice_region intron	N/A	ENSP00000412125.2	Q9C093-2

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1081 AN: 152076 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.00785 AC: 1745 AN: 222374 AF XY: 0.00846

Gnomad AFR exome AF: 0.00282

Gnomad AMR exome AF: 0.00294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000249

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00691

GnomAD4 exome AF: 0.0124 AC: 17811 AN: 1434504 Hom.: 142 Cov.: 30 AF XY: 0.0125 AC XY: 8938 AN XY: 713310

African (AFR) AF: 0.00195 AC: 61 AN: 31212

American (AMR) AF: 0.00339 AC: 122 AN: 35996

Ashkenazi Jewish (ASJ) AF: 0.0000815 AC: 2 AN: 24536

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39586

South Asian (SAS) AF: 0.0139 AC: 1123 AN: 80646

European-Finnish (FIN) AF: 0.00419 AC: 222 AN: 52952

Middle Eastern (MID) AF: 0.0100 AC: 56 AN: 5592

European-Non Finnish (NFE) AF: 0.0141 AC: 15578 AN: 1104946

Other (OTH) AF: 0.0108 AC: 640 AN: 59038

GnomAD4 genome AF: 0.00709 AC: 1079 AN: 152194 Hom.: 4 Cov.: 32 AF XY: 0.00669 AC XY: 498 AN XY: 74418

African (AFR) AF: 0.00217 AC: 90 AN: 41518

American (AMR) AF: 0.00249 AC: 38 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4820

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 821 AN: 68006

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.00897 Hom.: 2

Bravo AF: 0.00700

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.25
DANN	Benign	0.61
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.014
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: rs138022749; hg19: chr5-35771703;