Genetic Variant MOSPD3:p.Ile94Val (chr7-100613268-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_023948.5(MOSPD3):c.280A>G(p.Ile94Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000491 in 1,424,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

MOSPD3
NM_023948.5 missense, splice_region

Scores

Splicing: ADA: 0.9755

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.25

Publications

0 publications found

Variant links:

Genes affected

MOSPD3 (HGNC:25078): (motile sperm domain containing 3) This gene encodes a multi-pass membrane protein with a major sperm protein (MSP) domain. The deletion of a similar mouse gene is associated with defective cardiac development and neonatal lethality. Alternate transcriptional splice variants, encoding different isoforms, have been described. [provided by RefSeq, Jul 2008]

MOSPD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOSPD3	NM_023948.5 link	c.280A>G	p.Ile94Val	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000393950.7	NP_076438.1	O75425-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOSPD3	ENST00000393950.7 link	c.280A>G	p.Ile94Val	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_023948.5	ENSP00000377522.2		O75425-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251396

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

GnomAD4 exome

AF:

0.00000491

AC:

AN:

1424250

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

709060

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32536

American (AMR)

AF:

0.000113

AC:

AN:

44072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25224

East Asian (EAS)

AF:

0.00

AC:

AN:

38474

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083954

Other (OTH)

AF:

0.0000171

AC:

AN:

58436

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.280A>G (p.I94V) alteration is located in exon 2 (coding exon 2) of the MOSPD3 gene. This alteration results from a A to G substitution at nucleotide position 280, causing the isoleucine (I) at amino acid position 94 to be replaced by a valine (V). 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

0.32

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.;T;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.059

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.84

.;T;D;.;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.5

L;.;L;L;L

PhyloP100

4.2

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.90

N;N;N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0060

D;D;D;D;D

Sift4G

Benign

0.077

T;T;T;T;D

Polyphen

0.0

B;.;B;B;.

Vest4

0.48

MutPred

0.75

Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);

MVP

0.69

MPC

0.26

ClinPred

0.58

GERP RS

3.8

Varity_R

0.17

gMVP

0.11

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

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7-100613268-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over