7-141745501-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_003143.3(SSBP1):c.320G>A(p.Arg107Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SSBP1 NM_003143.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.50

Genes affected

SSBP1 (HGNC:11317): (single stranded DNA binding protein 1) SSBP1 is a housekeeping gene involved in mitochondrial biogenesis (Tiranti et al., 1995 [PubMed 7789991]). It is also a subunit of a single-stranded DNA (ssDNA)-binding complex involved in the maintenance of genome stability (Huang et al., 2009) [PubMed 19683501].[supplied by OMIM, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain SSB (size 111) in uniprot entity SSBP_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003143.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-141745501-G-A is Pathogenic according to our data. Variant chr7-141745501-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 977503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-141745501-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SSBP1	NM_003143.3	c.320G>A	p.Arg107Gln	missense_variant	6/7	ENST00000265304.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SSBP1	ENST00000265304.11	c.320G>A	p.Arg107Gln	missense_variant	6/7	1	NM_003143.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Optic atrophy 13 with retinal and foveal abnormalities Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:31298765). In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.24; 3Cnet: 0.14). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SSBP1 related disorder (ClinVar ID: VCV000977503 / PMID: 31298765 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID:31298765). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 17, 2024	Criteria applied: PS4,PS3_MOD,PS2_MOD,PM2_SUP,PP1 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;T;T;T;T;T;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.20	N;N;N;.;N;.;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D;.;D;D;D;D;D;D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D
Sift4G	Benign	0.077	T;T;T;T;T;T;T;T
Polyphen		0.98	D;D;D;.;D;.;D;D
Vest4		0.58
MutPred		0.54		Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);
MVP		0.62
MPC		0.79
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1799747454; hg19: chr7-141445301; COSMIC: COSV54680821; COSMIC: COSV54680821;