Genetic Variant SPACA4:p.Pro120Leu (chr19-48607337-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_133498.3(SPACA4):c.359C>T(p.Pro120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SPACA4
NM_133498.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.17

Publications

0 publications found

Variant links:

Genes affected

SPACA4 (HGNC:16441): (sperm acrosome associated 4) Predicted to be involved in cell adhesion. Predicted to be located in extracellular region and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SPACA4 links:

FAM83E (HGNC:25972): (family with sequence similarity 83 member E) Enables protein kinase binding activity. Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

FAM83E links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04212421).

BP6

Variant 19-48607337-C-T is Benign according to our data. Variant chr19-48607337-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2238066.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133498.3. 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
	SPACA4	NM_133498.3	MANE Select	c.359C>T	p.Pro120Leu	missense	Exon 1 of 1	NP_598005.1	Q8TDM5
	FAM83E	NM_017708.4	MANE Select	c.758+2539G>A		intron	N/A	NP_060178.2	Q2M2I3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPACA4	ENST00000321762.3	TSL:6 MANE Select	c.359C>T	p.Pro120Leu	missense	Exon 1 of 1	ENSP00000312774.1	Q8TDM5
FAM83E	ENST00000263266.4	TSL:1 MANE Select	c.758+2539G>A		intron	N/A	ENSP00000263266.2	Q2M2I3
FAM83E	ENST00000876133.1		c.758+2539G>A		intron	N/A	ENSP00000546192.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000476

AC:

AN:

210042

AF XY:

0.00000876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000323

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

Data not reliable, filtered out with message: AS_VQSR

AF:

6.95e-7

AC:

AN:

1439028

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714152

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33104

American (AMR)

AF:

0.0000239

AC:

AN:

41920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25572

East Asian (EAS)

AF:

0.00

AC:

AN:

38680

South Asian (SAS)

AF:

0.00

AC:

AN:

83578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100148

Other (OTH)

AF:

0.00

AC:

AN:

59398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.014

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.0042

LIST_S2

Benign

0.43

M_CAP

Benign

0.010

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

1.2

PrimateAI

Benign

0.31

PROVEAN

Benign

1.5

REVEL

Benign

0.073

Sift

Pathogenic

0.0

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.091

MutPred

0.17

Loss of loop (P = 0.0112)

MVP

0.043

MPC

0.68

ClinPred

0.21

GERP RS

-0.067

Varity_R

0.079

gMVP

0.36

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over