5-35641438-A-G

Position:

• chr5-35641438-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024867.4(SPEF2):​c.169A>G​(p.Ser57Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SPEF2 NM_024867.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082054496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPEF2	NM_024867.4	c.169A>G	p.Ser57Gly	missense_variant	3/37	ENST00000356031.8	NP_079143.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPEF2	ENST00000356031.8	c.169A>G	p.Ser57Gly	missense_variant	3/37	1	NM_024867.4	ENSP00000348314.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459482 Hom.: 0 Cov.: 29 AF XY: 0.00000964 AC XY: 7 AN XY: 725846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2024

The c.169A>G (p.S57G) alteration is located in exon 3 (coding exon 3) of the SPEF2 gene. This alteration results from a A to G substitution at nucleotide position 169, causing the serine (S) at amino acid position 57 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	.;.;T;T;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.66	T;T;T;T;T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.082	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.;N;.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N;.;N;N;N
REVEL	Benign	0.028
Sift	Benign	0.18	T;T;.;T;T;T
Sift4G	Benign	0.38	T;T;.;T;T;T
Polyphen		0.20	B;B;.;B;.;.
Vest4		0.054
MutPred		0.50		Loss of phosphorylation at S57 (P = 0.029);Loss of phosphorylation at S57 (P = 0.029);Loss of phosphorylation at S57 (P = 0.029);Loss of phosphorylation at S57 (P = 0.029);Loss of phosphorylation at S57 (P = 0.029);Loss of phosphorylation at S57 (P = 0.029);
MVP		0.030
MPC		0.029
ClinPred		0.32	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.092

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-35641540;