Genetic Variant MOSPD3:p.Ile94Leu (chr7-100613268-A-C) – 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>C(p.Ile94Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000665 in 150,486 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

MOSPD3
NM_023948.5 missense, splice_region

Scores

Splicing: ADA: 0.9973

Clinical Significance

Not reported in ClinVar

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:

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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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023948.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MOSPD3	NM_023948.5	MANE Select	c.280A>C	p.Ile94Leu	missense splice_region	Exon 2 of 5	NP_076438.1	O75425-1
MOSPD3	NM_001040097.2		c.280A>C	p.Ile94Leu	missense splice_region	Exon 3 of 6	NP_001035186.1	O75425-1
MOSPD3	NM_001040098.1		c.280A>C	p.Ile94Leu	missense splice_region	Exon 3 of 6	NP_001035187.1	O75425-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MOSPD3	ENST00000393950.7	TSL:1 MANE Select	c.280A>C	p.Ile94Leu	missense splice_region	Exon 2 of 5	ENSP00000377522.2	O75425-1
MOSPD3	ENST00000424091.2	TSL:1	c.280A>C	p.Ile94Leu	missense splice_region	Exon 2 of 5	ENSP00000404626.2	O75425-4
MOSPD3	ENST00000921523.1		c.280A>C	p.Ile94Leu	missense splice_region	Exon 2 of 5	ENSP00000591582.1

Frequencies

GnomAD3 genomes

AF:

0.00000665

AC:

AN:

150486

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000665

AC:

AN:

150486

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73486

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41178

American (AMR)

AF:

0.00

AC:

AN:

15140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

4982

South Asian (SAS)

AF:

0.00

AC:

AN:

4632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67608

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.12

Eigen_PC

Benign

0.015

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.5

PhyloP100

4.2

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.33

Sift

Uncertain

0.0040

Sift4G

Benign

0.095

Polyphen

0.0010

Vest4

0.67

MutPred

0.77

Loss of sheet (P = 0.1398)

MVP

0.80

MPC

0.32

ClinPred

0.76

GERP RS

3.8

Varity_R

0.35

gMVP

0.30

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over