6-112350349-A-T

Variant names:

• chr6-112350349-A-T
• rs1173257704
• NM_001013734.3:c.641A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001013734.3(RFPL4B):​c.641A>T​(p.Asp214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RFPL4B NM_001013734.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

Genes affected

RFPL4B (HGNC:33264): (ret finger protein like 4B) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL4B	NM_001013734.3	c.641A>T	p.Asp214Val	missense_variant	Exon 3 of 3	ENST00000441065.3	NP_001013756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFPL4B	ENST00000441065.3	c.641A>T	p.Asp214Val	missense_variant	Exon 3 of 3	2	NM_001013734.3	ENSP00000423391.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251432 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.641A>T (p.D214V) alteration is located in exon 3 (coding exon 1) of the RFPL4B gene. This alteration results from a A to T substitution at nucleotide position 641, causing the aspartic acid (D) at amino acid position 214 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.17
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.29
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.30
MutPred		0.62		Loss of solvent accessibility (P = 0.0544);
MVP		0.72
MPC		0.64
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.31
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs1173257704; hg19: chr6-112671551;