chr7-141745501-G-A

Variant names:

• chr7-141745501-G-A
• rs1799747454
• NM_003143.3:c.320G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PP2 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 (★★). ClinVar reports functional evidence for this variant: "SCV002521243: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:31298765).; SCV006082993: A functional study of the p.Arg107Gln variant in zebrafish demonstrated a deleterious effect on retinal development likely due to a dominant-negative mechanism (Jurkute et al., 2019).; SCV005328018: Published functional studies suggest a damaging effect (PMID:31550240, 31298765)".

• Frequency: Genomes: not found (cov: 33)
• Consequence: SSBP1 NM_003143.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.50
• Publications: 4 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002521243: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:31298765).; SCV006082993: A functional study of the p.Arg107Gln variant in zebrafish demonstrated a deleterious effect on retinal development likely due to a dominant-negative mechanism (Jurkute et al., 2019).; SCV005328018: Published functional studies suggest a damaging effect (PMID: 31550240, 31298765)
• 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 optic atrophy 13 with retinal and foveal abnormalities, Leigh syndrome.
• PP5: Variant 7-141745501-G-A is Pathogenic according to our data. Variant chr7-141745501-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 977503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.320G>A	p.Arg107Gln	missense	Exon 6 of 7	NP_003134.1	A4D1U3
	SSBP1	NM_001256510.1		c.320G>A	p.Arg107Gln	missense	Exon 6 of 7	NP_001243439.1	Q04837
	SSBP1	NM_001256511.1		c.320G>A	p.Arg107Gln	missense	Exon 6 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.320G>A	p.Arg107Gln	missense	Exon 6 of 7	ENSP00000265304.6	Q04837
	SSBP1	ENST00000481508.1	TSL:1	c.320G>A	p.Arg107Gln	missense	Exon 6 of 7	ENSP00000419665.1	Q04837
	SSBP1	ENST00000498107.5	TSL:1	c.320G>A	p.Arg107Gln	missense	Exon 6 of 7	ENSP00000419541.1	Q04837

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Optic atrophy 13 with retinal and foveal abnormalities (6)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.20	N
PhyloP100		8.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.077	T
Polyphen		0.98	D
Vest4		0.58
MutPred		0.54		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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

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