7-141743588-G-A

Variant names:

• chr7-141743588-G-A
• rs1799652893
• NM_003143.3:c.113G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_003143.3(SSBP1):​c.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SSBP1 NM_003143.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.88
• Publications: 1 publications found

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]

SSBP1 Gene-Disease associations (from GenCC):

• optic atrophy 13 with retinal and foveal abnormalities

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, Ambry Genetics
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a chain Single-stranded DNA-binding protein, mitochondrial (size 131) in uniprot entity SSBP_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003143.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.1089 (below the threshold of 3.09). Trascript score misZ: 1.4851 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, optic atrophy 13 with retinal and foveal abnormalities.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 7-141743588-G-A is Pathogenic according to our data. Variant chr7-141743588-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 977502.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003143.3. 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
	SSBP1	NM_003143.3	MANE Select	c.113G>A	p.Arg38Gln	missense	Exon 4 of 7	NP_003134.1	A4D1U3
	SSBP1	NM_001256510.1		c.113G>A	p.Arg38Gln	missense	Exon 4 of 7	NP_001243439.1	Q04837
	SSBP1	NM_001256511.1		c.113G>A	p.Arg38Gln	missense	Exon 4 of 7	NP_001243440.1	A4D1U3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSBP1	ENST00000265304.11	TSL:1 MANE Select	c.113G>A	p.Arg38Gln	missense	Exon 4 of 7	ENSP00000265304.6	Q04837
	SSBP1	ENST00000481508.1	TSL:1	c.113G>A	p.Arg38Gln	missense	Exon 4 of 7	ENSP00000419665.1	Q04837
	SSBP1	ENST00000498107.5	TSL:1	c.113G>A	p.Arg38Gln	missense	Exon 4 of 7	ENSP00000419541.1	Q04837

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cone-rod dystrophy (1)
1	-	-	Optic atrophy 13 with retinal and foveal abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.66		Loss of MoRF binding (P = 0.0164)
MVP		0.73
MPC		1.1
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.82
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1799652893; hg19: chr7-141443388; COSMIC: COSV54681057; COSMIC: COSV54681057;