NM_016492.5:c.67A>T

Variant names:

• chr17-8288855-A-T
• rs371469933
• NM_016492.5:c.67A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016492.5(RANGRF):​c.67A>T​(p.Ile23Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I23V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RANGRF NM_016492.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.67A>T	p.Ile23Phe	missense	Exon 1 of 5	NP_057576.2
	RANGRF	NM_001177802.2		c.67A>T	p.Ile23Phe	missense	Exon 1 of 3	NP_001171273.1	Q9HD47-3
	RANGRF	NM_001177801.2		c.67A>T	p.Ile23Phe	missense	Exon 1 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.67A>T	p.Ile23Phe	missense	Exon 1 of 5	ENSP00000226105.6	Q9HD47-1
	RANGRF	ENST00000439238.3	TSL:1	c.67A>T	p.Ile23Phe	missense	Exon 1 of 3	ENSP00000413190.3	Q9HD47-3
	RANGRF	ENST00000407006.8	TSL:1	c.67A>T	p.Ile23Phe	missense	Exon 1 of 4	ENSP00000383940.4	Q9HD47-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250688 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

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	0.15
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.099
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	-0.043	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.54
Sift	Benign	0.079	T
Sift4G	Benign	0.15	T
Polyphen		0.64	P
Vest4		0.32
MutPred		0.62		Loss of catalytic residue at L28 (P = 0.0173)
MVP		0.81
MPC		0.72
ClinPred		0.94	D
GERP RS		1.8
PromoterAI		-0.073	Neutral
Varity_R		0.20
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371469933; hg19: chr17-8192173;