chr5-35700744-A-G

Variant names:

• chr5-35700744-A-G
• rs201730485
• NM_024867.4:c.2390A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_024867.4(SPEF2):​c.2390A>G​(p.Asp797Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,613,526 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.520
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008966774).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000453 (69/152374) while in subpopulation NFE AF = 0.000882 (60/68034). AF 95% confidence interval is 0.000703. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.2390A>G	p.Asp797Gly	missense	Exon 16 of 37	NP_079143.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPEF2	ENST00000356031.8	TSL:1 MANE Select	c.2390A>G	p.Asp797Gly	missense	Exon 16 of 37	ENSP00000348314.3	Q9C093-1
	SPEF2	ENST00000509059.5	TSL:1	c.2375A>G	p.Asp792Gly	missense	Exon 16 of 19	ENSP00000421593.1	D6REZ4
	SPEF2	ENST00000637569.1	TSL:5	c.2390A>G	p.Asp797Gly	missense	Exon 16 of 35	ENSP00000490886.1	A0A1B0GWD8

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000442 AC: 110 AN: 248654 AF XY: 0.000526

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000816 AC: 1192 AN: 1461152 Hom.: 2 Cov.: 34 AF XY: 0.000810 AC XY: 589 AN XY: 726810

African (AFR) AF: 0.000209 AC: 7 AN: 33454

American (AMR) AF: 0.000201 AC: 9 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86228

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53378

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.000941 AC: 1046 AN: 1111528

Other (OTH) AF: 0.000646 AC: 39 AN: 60348

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74524

African (AFR) AF: 0.0000481 AC: 2 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000746 Hom.: 1

Bravo AF: 0.000461

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000272 AC: 1

ESP6500EA AF: 0.00123 AC: 10

ExAC AF: 0.000472 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.52
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.077
Sift	Benign	0.66	T
Sift4G	Benign	0.68	T
Polyphen		0.0030	B
Vest4		0.12
MVP		0.19
MPC		0.034
ClinPred		0.015	T
GERP RS		3.7
Varity_R		0.094
gMVP		0.36
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201730485; hg19: chr5-35700846;