Genetic Variant SSBP4:p.Glu19Asp (chr19-18419705-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032627.5(SSBP4):c.57G>C(p.Glu19Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,025,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

SSBP4
NM_032627.5 missense, splice_region

Scores

Splicing: ADA: 0.3035

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.630

Variant links:

Genes affected

SSBP4 (HGNC:15676): (single stranded DNA binding protein 4) Predicted to enable single-stranded DNA binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Predicted to be integral component of membrane. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SSBP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17344612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSBP4	NM_032627.5 link	c.57G>C	p.Glu19Asp	missense_variant, splice_region_variant	Exon 1 of 18	ENST00000270061.12	NP_116016.1	Q9BWG4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSBP4	ENST00000270061.12 link	c.57G>C	p.Glu19Asp	missense_variant, splice_region_variant	Exon 1 of 18	1	NM_032627.5	ENSP00000270061.5		Q9BWG4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000195

AC:

AN:

1025682

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

487614

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

20282

American (AMR)

AF:

0.00

AC:

AN:

6114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11016

East Asian (EAS)

AF:

0.00

AC:

AN:

19616

South Asian (SAS)

AF:

0.00

AC:

AN:

24198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3508

European-Non Finnish (NFE)

AF:

0.00000113

AC:

AN:

882960

Other (OTH)

AF:

0.0000259

AC:

AN:

38678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.57G>C (p.E19D) alteration is located in exon 1 (coding exon 1) of the SSBP4 gene. This alteration results from a G to C substitution at nucleotide position 57, causing the glutamic acid (E) at amino acid position 19 to be replaced by an aspartic acid (D). 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

Pathogenic

0.98

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.1

M;M;.

PhyloP100

0.63

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.7

N;N;.

REVEL

Benign

0.13

Sift

Benign

0.053

T;D;.

Sift4G

Uncertain

0.032

D;D;.

Polyphen

0.0040

.;B;.

Vest4

0.33

MutPred

0.21

Loss of ubiquitination at K20 (P = 0.0502);Loss of ubiquitination at K20 (P = 0.0502);Loss of ubiquitination at K20 (P = 0.0502);

MVP

0.093

MPC

0.19

ClinPred

0.59

GERP RS

2.1

PromoterAI

-0.098

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.28

gMVP

0.39

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.30

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.0

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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19-18419705-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over