rs72619327

Variant names:

• chr9-133352593-C-G
• rs72619327
• NM_003172.4:c.604G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-133352593-C-G
• chr9-133352593-C-A
• chr9-133352593-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BA1

The NM_003172.4(SURF1):​c.604G>C​(p.Asp202His) variant causes a missense change. The variant allele was found at a frequency of 0.00514 in 1,614,146 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D202D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (80 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (359 hom.)
• Consequence: SURF1 NM_003172.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.82
• Publications: 19 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 -10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003172.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.68006 (below the threshold of 3.09). Trascript score misZ: -1.3185 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex IV deficiency, nuclear type 1, Leigh syndrome, mitochondrial disease, Charcot-Marie-Tooth disease type 4K, Leigh syndrome with leukodystrophy, Leigh syndrome with cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0063804686).
• BP6: Variant 9-133352593-C-G is Benign according to our data. Variant chr9-133352593-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 139375.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 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.604G>C	p.Asp202His	missense	Exon 7 of 9	NP_003163.1	Q15526-1
	SURF1	NM_001280787.1		c.277G>C	p.Asp93His	missense	Exon 6 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.604G>C	p.Asp202His	missense	Exon 7 of 9	ENSP00000361042.3	Q15526-1
	SURF1	ENST00000615505.4	TSL:1	c.277G>C	p.Asp93His	missense	Exon 6 of 8	ENSP00000482067.1	A0A087WYS9
	SURF1	ENST00000886676.1		c.574G>C	p.Asp192His	missense	Exon 7 of 9	ENSP00000556735.1

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1045 AN: 152180 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0143 AC: 3584 AN: 251146 AF XY: 0.0129

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00496 AC: 7253 AN: 1461848 Hom.: 359 Cov.: 32 AF XY: 0.00482 AC XY: 3505 AN XY: 727208

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.0142 AC: 635 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26136

East Asian (EAS) AF: 0.126 AC: 4986 AN: 39698

South Asian (SAS) AF: 0.00376 AC: 324 AN: 86254

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53416

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.000517 AC: 575 AN: 1111996

Other (OTH) AF: 0.0102 AC: 617 AN: 60392

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152298 Hom.: 80 Cov.: 33 AF XY: 0.00745 AC XY: 555 AN XY: 74458

African (AFR) AF: 0.00147 AC: 61 AN: 41558

American (AMR) AF: 0.00810 AC: 124 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.151 AC: 780 AN: 5182

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68030

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00808

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0132 AC: 1601

Asia WGS AF: 0.0650 AC: 226 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Leigh syndrome (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.97	D
Vest4		0.24
MPC		0.17
ClinPred		0.027	T
GERP RS		5.4
Varity_R		0.46
gMVP		0.64
Mutation Taster		=86/14	polymorphism (auto)

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: rs72619327; hg19: chr9-136219448; COSMIC: COSV59298602; COSMIC: COSV59298602;