Genetic Variant NM_017503.5:c.69C>T (chr9-133356661-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_017503.5(SURF2):c.69C>T(p.Asp23Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,520,880 control chromosomes in the GnomAD database, including 188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.015 ( 174 hom. )

Consequence

SURF2
NM_017503.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.819

Publications

2 publications found

Variant links:

Genes affected

SURF2 (HGNC:11475): (surfeit 2) This gene shares a bidirectional promoter with surfeit 1 (SURF1; GeneID: 6834), which is located on the opposite strand. It encodes a conserved protein that is expressed in a variety of tissues. [provided by RefSeq, Jul 2013]

SURF2 links:

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

SURF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 9-133356661-C-T is Benign according to our data. Variant chr9-133356661-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1211958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.819 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0114 (1734/152152) while in subpopulation EAS AF = 0.0182 (94/5154). AF 95% confidence interval is 0.0153. There are 14 homozygotes in GnomAd4. There are 850 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017503.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF2	NM_017503.5	MANE Select	c.69C>T	p.Asp23Asp	synonymous	Exon 1 of 6	NP_059973.4
SURF2	NM_001278928.2		c.69C>T	p.Asp23Asp	synonymous	Exon 1 of 6	NP_001265857.1
SURF1	NM_003172.4	MANE Select	c.-208G>A		upstream_gene	N/A	NP_003163.1	Q15526-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SURF2	ENST00000371964.5	TSL:1 MANE Select	c.69C>T	p.Asp23Asp	synonymous	Exon 1 of 6	ENSP00000361032.4	Q15527
SURF2	ENST00000934438.1		c.69C>T	p.Asp23Asp	synonymous	Exon 1 of 7	ENSP00000604497.1
SURF2	ENST00000875735.1		c.69C>T	p.Asp23Asp	synonymous	Exon 1 of 6	ENSP00000545794.1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1734

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00348

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.00896

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.0182

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0191

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0157

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0117

AC:

1367

AN:

116824

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.00409

Gnomad AMR exome

AF:

0.00695

Gnomad ASJ exome

AF:

0.00657

Gnomad EAS exome

AF:

0.0193

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0151

AC:

20733

AN:

1368728

Hom.:

174

Cov.:

AF XY:

0.0147

AC XY:

9893

AN XY:

675208

show subpopulations

African (AFR)

AF:

0.00259

AC:

AN:

29694

American (AMR)

AF:

0.00795

AC:

272

AN:

34224

Ashkenazi Jewish (ASJ)

AF:

0.00590

AC:

144

AN:

24398

East Asian (EAS)

AF:

0.0241

AC:

824

AN:

34142

South Asian (SAS)

AF:

0.00359

AC:

280

AN:

77890

European-Finnish (FIN)

AF:

0.0162

AC:

544

AN:

33566

Middle Eastern (MID)

AF:

0.00579

AC:

AN:

4660

European-Non Finnish (NFE)

AF:

0.0165

AC:

17718

AN:

1073008

Other (OTH)

AF:

0.0148

AC:

847

AN:

57146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1161

2322

3484

4645

5806

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

698

1396

2094

2792

3490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0114

AC:

1734

AN:

152152

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

850

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00347

AC:

144

AN:

41506

American (AMR)

AF:

0.00895

AC:

137

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3470

East Asian (EAS)

AF:

0.0182

AC:

AN:

5154

South Asian (SAS)

AF:

0.00373

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0191

AC:

202

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0157

AC:

1069

AN:

67982

Other (OTH)

AF:

0.0152

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0125

Hom.:

Bravo

AF:

0.0109

Asia WGS

AF:

0.0230

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

-0.82

PromoterAI

0.0020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over