rs140704891

Variant names:

• chr17-8289059-G-T
• rs140704891
• NM_016492.5:c.181G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-8289059-G-T
• chr17-8289059-G-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_016492.5(RANGRF):​c.181G>T​(p.Glu61*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,690 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (27 hom.)
• Consequence: RANGRF NM_016492.5 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.19
• Publications: 25 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 17-8289059-G-T is Benign according to our data. Variant chr17-8289059-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 190845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 551 AD,Unknown 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.181G>T	p.Glu61*	stop_gained	Exon 2 of 5	NP_057576.2
	RANGRF	NM_001177802.2		c.181G>T	p.Glu61*	stop_gained	Exon 2 of 3	NP_001171273.1	Q9HD47-3
	RANGRF	NM_001177801.2		c.181G>T	p.Glu61*	stop_gained	Exon 2 of 4	NP_001171272.1	Q9HD47-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANGRF	ENST00000226105.11	TSL:1 MANE Select	c.181G>T	p.Glu61*	stop_gained	Exon 2 of 5	ENSP00000226105.6	Q9HD47-1
	RANGRF	ENST00000439238.3	TSL:1	c.181G>T	p.Glu61*	stop_gained	Exon 2 of 3	ENSP00000413190.3	Q9HD47-3
	RANGRF	ENST00000407006.8	TSL:1	c.181G>T	p.Glu61*	stop_gained	Exon 2 of 4	ENSP00000383940.4	Q9HD47-2

Frequencies

GnomAD3 genomes AF: 0.00362 AC: 551 AN: 152238 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00988

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00400 AC: 996 AN: 248904 AF XY: 0.00390

Gnomad AFR exome AF: 0.000750

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00562

Gnomad OTH exome AF: 0.00541

GnomAD4 exome AF: 0.00458 AC: 6693 AN: 1461334 Hom.: 27 Cov.: 32 AF XY: 0.00452 AC XY: 3284 AN XY: 726980

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00189 AC: 163 AN: 86256

European-Finnish (FIN) AF: 0.0104 AC: 552 AN: 52972

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00508 AC: 5650 AN: 1111934

Other (OTH) AF: 0.00399 AC: 241 AN: 60378

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152356 Hom.: 2 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74498

African (AFR) AF: 0.000842 AC: 35 AN: 41590

American (AMR) AF: 0.00105 AC: 16 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00988 AC: 105 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00534 AC: 363 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00432 Hom.: 2

Bravo AF: 0.00298

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00395 AC: 479

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00551

EpiControl AF: 0.00486

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Cardiac arrhythmia (1)
-	-	1	RANGRF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		2.2
Vest4		0.27
GERP RS		4.4
PromoterAI		0.092	Neutral
Mutation Taster		=68/132	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -10

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

Other links and lift over

dbSNP: rs140704891; hg19: chr17-8192377; COSMIC: COSV56840201; COSMIC: COSV56840201;