Genetic Variant SLC25A35:c.*43-188G>A (chr17-8288620-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201520.3(SLC25A35):c.*996G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 775,368 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 129 hom., cov: 32)

Exomes 𝑓: 0.020 ( 195 hom. )

Consequence

SLC25A35
NM_201520.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.02

Publications

3 publications found

Variant links:

Genes affected

SLC25A35 (HGNC:31921): (solute carrier family 25 member 35) SLC25A35 belongs to the SLC25 family of mitochondrial carrier proteins (Haitina et al., 2006 [PubMed 16949250]).[supplied by OMIM, Mar 2008]

SLC25A35 links:

RANGRF (HGNC:17679): (RAN guanine nucleotide release factor) This gene encodes a protein that has been shown to function as a guanine nucleotide release factor in mouse and to regulate the expression and function of the Nav1.5 cardiac sodium channel in human. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

RANGRF Gene-Disease associations (from GenCC):

Brugada syndrome
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp

RANGRF 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=-0.68).

BP6

Variant 17-8288620-C-T is Benign according to our data. Variant chr17-8288620-C-T is described in ClinVar as Benign. ClinVar VariationId is 1224078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201520.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC25A35	NM_201520.3	c.*996G>A	3_prime_UTR	Exon 6 of 6	NP_958928.1	Q3KQZ1-4
SLC25A35	NM_001320871.2	c.*43-188G>A	intron	N/A	NP_001307800.1	Q3KQZ1-4
SLC25A35	NR_135483.2	n.2541G>A	non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC25A35	ENST00000579192.5	TSL:1	c.*43-188G>A	intron	N/A	ENSP00000462395.1	Q3KQZ1-4
SLC25A35	ENST00000380067.6	TSL:2	c.*996G>A	3_prime_UTR	Exon 6 of 6	ENSP00000369407.2	Q3KQZ1-4
SLC25A35	ENST00000581320.1	TSL:3	n.91-188G>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4883

AN:

152160

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0367

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0229

GnomAD4 exome

AF:

0.0200

AC:

12462

AN:

623090

Hom.:

195

Cov.:

AF XY:

0.0204

AC XY:

6759

AN XY:

331538

show subpopulations

African (AFR)

AF:

0.0659

AC:

1069

AN:

16222

American (AMR)

AF:

0.0148

AC:

456

AN:

30718

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

226

AN:

18824

East Asian (EAS)

AF:

0.00130

AC:

AN:

32280

South Asian (SAS)

AF:

0.0359

AC:

2234

AN:

62158

European-Finnish (FIN)

AF:

0.0208

AC:

708

AN:

34016

Middle Eastern (MID)

AF:

0.0457

AC:

174

AN:

3806

European-Non Finnish (NFE)

AF:

0.0173

AC:

6810

AN:

392892

Other (OTH)

AF:

0.0231

AC:

743

AN:

32174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

671

1343

2014

2686

3357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.0323

AC:

4911

AN:

152278

Hom.:

129

Cov.:

AF XY:

0.0325

AC XY:

2421

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0654

AC:

2718

AN:

41542

American (AMR)

AF:

0.0235

AC:

360

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3472

East Asian (EAS)

AF:

0.00347

AC:

AN:

5182

South Asian (SAS)

AF:

0.0369

AC:

178

AN:

4824

European-Finnish (FIN)

AF:

0.0250

AC:

265

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0186

AC:

1267

AN:

68028

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

252

504

756

1008

1260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.0274

Hom.:

Bravo

AF:

0.0333

Asia WGS

AF:

0.0540

AC:

188

AN:

3478

ClinVar

ClinVar submissions

Significance: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

-0.68

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

2.0

PromoterAI

0.011

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(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