Genetic Variant SURF2:c.-23G>C (chr9-133356570-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017503.5(SURF2):c.-23G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000836 in 1,514,910 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 24 hom. )

Consequence

SURF2
NM_017503.5 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00400

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 9-133356570-G-C is Benign according to our data. Variant chr9-133356570-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1198865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000732 (997/1362724) while in subpopulation AMR AF = 0.0226 (772/34128). AF 95% confidence interval is 0.0213. There are 24 homozygotes in GnomAdExome4. There are 423 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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	Effect	Exon Rank	Protein	UniProt
SURF2	NM_017503.5	MANE Select	c.-23G>C	5_prime_UTR	Exon 1 of 6	NP_059973.4
SURF2	NM_001278928.2		c.-23G>C	5_prime_UTR	Exon 1 of 6	NP_001265857.1
SURF1	NM_003172.4	MANE Select	c.-117C>G	upstream_gene	N/A	NP_003163.1	Q15526-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SURF2	ENST00000371964.5	TSL:1 MANE Select	c.-23G>C	5_prime_UTR	Exon 1 of 6	ENSP00000361032.4	Q15527
SURF2	ENST00000875735.1		c.-23G>C	5_prime_UTR	Exon 1 of 6	ENSP00000545794.1
SURF2	ENST00000934434.1		c.-23G>C	5_prime_UTR	Exon 1 of 6	ENSP00000604494.1

Frequencies

GnomAD3 genomes

AF:

0.00178

AC:

270

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00751

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00529

AC:

584

AN:

110308

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0218

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00967

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.000732

AC:

997

AN:

1362724

Hom.:

Cov.:

AF XY:

0.000629

AC XY:

423

AN XY:

672138

show subpopulations

African (AFR)

AF:

0.000141

AC:

AN:

28304

American (AMR)

AF:

0.0226

AC:

772

AN:

34128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24242

East Asian (EAS)

AF:

0.00385

AC:

126

AN:

32698

South Asian (SAS)

AF:

0.0000258

AC:

AN:

77578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4310

European-Non Finnish (NFE)

AF:

0.0000121

AC:

AN:

1071164

Other (OTH)

AF:

0.00141

AC:

AN:

56922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00177

AC:

269

AN:

152186

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41558

American (AMR)

AF:

0.0140

AC:

214

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00753

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67940

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00114

Hom.:

Bravo

AF:

0.00371

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

-0.82

CADD

Benign

7.7

(source)

DANN

Benign

0.55

PhyloP100

0.0040

PromoterAI

0.26

Neutral

(source)

Mutation Taster

=300/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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