19-18431408-C-G

Variant names:

• chr19-18431408-C-G
• rs751838128
• NM_032627.5:c.425C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032627.5(SSBP4):​c.425C>G​(p.Pro142Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000293 in 1,363,340 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P142L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SSBP4 NM_032627.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032627.5. 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
	SSBP4	NM_032627.5	MANE Select	c.425C>G	p.Pro142Arg	missense	Exon 6 of 18	NP_116016.1	Q9BWG4-1
	SSBP4	NM_001009998.4		c.370-239C>G		intron	N/A	NP_001009998.1	Q9BWG4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSBP4	ENST00000270061.12	TSL:1 MANE Select	c.425C>G	p.Pro142Arg	missense	Exon 6 of 18	ENSP00000270061.5	Q9BWG4-1
	SSBP4	ENST00000867041.1		c.425C>G	p.Pro142Arg	missense	Exon 6 of 17	ENSP00000537100.1
	SSBP4	ENST00000915353.1		c.425C>G	p.Pro142Arg	missense	Exon 6 of 17	ENSP00000585412.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000293 AC: 4 AN: 1363340 Hom.: 0 Cov.: 25 AF XY: 0.00000442 AC XY: 3 AN XY: 678604

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

African (AFR) AF: 0.00 AC: 0 AN: 29572

American (AMR) AF: 0.00 AC: 0 AN: 30100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23704

East Asian (EAS) AF: 0.00 AC: 0 AN: 37344

South Asian (SAS) AF: 0.00 AC: 0 AN: 76572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5082

European-Non Finnish (NFE) AF: 0.00000284 AC: 3 AN: 1054534

Other (OTH) AF: 0.0000177 AC: 1 AN: 56404

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000222786), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.11
Sift	Uncertain	0.026	D
Sift4G	Benign	0.083	T
Polyphen		0.96	D
Vest4		0.59
MutPred		0.50		Gain of MoRF binding (P = 0.0109)
MVP		0.043
MPC		0.53
ClinPred		0.86	D
GERP RS		1.3
Varity_R		0.10
gMVP		0.30
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs751838128; hg19: chr19-18542218;