17-8289585-C-T

Variant names:

• chr17-8289585-C-T
• rs201882524
• NM_016492.5:c.434C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_016492.5(RANGRF):​c.434C>T​(p.Pro145Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,611,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P145T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: RANGRF NM_016492.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24
• Publications: 3 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• BS2: High AC in GnomAd4 at 8 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016492.5. 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
	RANGRF	NM_016492.5	MANE Select	c.434C>T	p.Pro145Leu	missense	Exon 4 of 5	NP_057576.2
	RANGRF	NM_001177801.2		c.434C>T	p.Pro145Leu	missense	Exon 4 of 4	NP_001171272.1
	SLC25A35	NM_001320871.2		c.*31G>A		3_prime_UTR	Exon 6 of 7	NP_001307800.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANGRF	ENST00000226105.11	TSL:1 MANE Select	c.434C>T	p.Pro145Leu	missense	Exon 4 of 5	ENSP00000226105.6
	RANGRF	ENST00000407006.8	TSL:1	c.434C>T	p.Pro145Leu	missense	Exon 4 of 4	ENSP00000383940.4
	SLC25A35	ENST00000579192.5	TSL:1	c.*31G>A		3_prime_UTR	Exon 6 of 7	ENSP00000462395.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251022 AF XY: 0.000125

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1459758 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 725756

African (AFR) AF: 0.0000598 AC: 2 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1110238

Other (OTH) AF: 0.0000829 AC: 5 AN: 60280

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74280

African (AFR) AF: 0.0000724 AC: 3 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000898 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiac arrhythmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.77
MVP		0.93
MPC		0.82
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.69
gMVP		0.81
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201882524; hg19: chr17-8192903; COSMIC: COSV99873797; COSMIC: COSV99873797;