9-133352709-G-C

Variant names:

• chr9-133352709-G-C
• rs28715079
• NM_003172.4:c.573C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003172.4(SURF1):​c.573C>G​(p.Thr191Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,613,240 control chromosomes in the GnomAD database, including 1,677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.055 (283 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1394 hom.)
• Consequence: SURF1 NM_003172.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0950
• Publications: 7 publications found

Genes affected

SURF1 (HGNC:11474): (SURF1 cytochrome c oxidase assembly factor) This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency. [provided by RefSeq, Jul 2008]

SURF1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 4K

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-133352709-G-C is Benign according to our data. Variant chr9-133352709-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.095 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003172.4. 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
	SURF1	NM_003172.4	MANE Select	c.573C>G	p.Thr191Thr	synonymous	Exon 6 of 9	NP_003163.1	Q15526-1
	SURF1	NM_001280787.1		c.246C>G	p.Thr82Thr	synonymous	Exon 5 of 8	NP_001267716.1	A0A087WYS9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SURF1	ENST00000371974.8	TSL:1 MANE Select	c.573C>G	p.Thr191Thr	synonymous	Exon 6 of 9	ENSP00000361042.3	Q15526-1
	SURF1	ENST00000615505.4	TSL:1	c.246C>G	p.Thr82Thr	synonymous	Exon 5 of 8	ENSP00000482067.1	A0A087WYS9
	SURF1	ENST00000886676.1		c.543C>G	p.Thr181Thr	synonymous	Exon 6 of 9	ENSP00000556735.1

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 8311 AN: 152178 Hom.: 282 Cov.: 33

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0184

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0464

GnomAD2 exomes AF: 0.0387 AC: 9642 AN: 249408 AF XY: 0.0380

Gnomad AFR exome AF: 0.0892

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0420

GnomAD4 exome AF: 0.0398 AC: 58101 AN: 1460944 Hom.: 1394 Cov.: 32 AF XY: 0.0391 AC XY: 28421 AN XY: 726718

African (AFR) AF: 0.0898 AC: 3006 AN: 33462

American (AMR) AF: 0.0239 AC: 1067 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 1062 AN: 26104

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0223 AC: 1920 AN: 86100

European-Finnish (FIN) AF: 0.0665 AC: 3551 AN: 53370

Middle Eastern (MID) AF: 0.0532 AC: 294 AN: 5528

European-Non Finnish (NFE) AF: 0.0403 AC: 44828 AN: 1111704

Other (OTH) AF: 0.0393 AC: 2371 AN: 60340

GnomAD4 genome AF: 0.0546 AC: 8321 AN: 152296 Hom.: 283 Cov.: 33 AF XY: 0.0552 AC XY: 4107 AN XY: 74466

African (AFR) AF: 0.0913 AC: 3795 AN: 41550

American (AMR) AF: 0.0381 AC: 583 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 140 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4828

European-Finnish (FIN) AF: 0.0730 AC: 774 AN: 10604

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2718 AN: 68036

Other (OTH) AF: 0.0459 AC: 97 AN: 2114

Alfa AF: 0.0119 Hom.: 4

Bravo AF: 0.0532

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.0392

EpiControl AF: 0.0375

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Leigh syndrome (2)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease type 4K;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.20
DANN	Benign	0.75
PhyloP100		0.095
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28715079; hg19: chr9-136219564;