6-18399578-A-G

Variant names:

• chr6-18399578-A-G
• rs36005166
• NM_182757.4:c.44A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_182757.4(RNF144B):​c.44A>G​(p.Glu15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,164 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: RNF144B NM_182757.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 2 publications found

Genes affected

RNF144B (HGNC:21578): (ring finger protein 144B) Enables ubiquitin-protein transferase activity. Involved in negative regulation of apoptotic process and ubiquitin-dependent protein catabolic process. Located in mitochondrial membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058307946).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF144B	NM_182757.4	c.44A>G	p.Glu15Gly	missense_variant	Exon 2 of 8	ENST00000259939.4	NP_877434.2
RNF144B	XM_047418594.1	c.44A>G	p.Glu15Gly	missense_variant	Exon 1 of 6		XP_047274550.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF144B	ENST00000259939.4	c.44A>G	p.Glu15Gly	missense_variant	Exon 2 of 8	1	NM_182757.4	ENSP00000259939.4
RNF144B	ENST00000486622.1	n.197A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00159

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000688 AC: 173 AN: 251452 AF XY: 0.000706

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00145 AC: 2125 AN: 1461874 Hom.: 4 Cov.: 32 AF XY: 0.00140 AC XY: 1021 AN XY: 727240

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00180 AC: 1997 AN: 1111994

Other (OTH) AF: 0.00141 AC: 85 AN: 60396

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74476

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.000899

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.000535 AC: 65

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00107

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44A>G (p.E15G) alteration is located in exon 2 (coding exon 1) of the RNF144B gene. This alteration results from a A to G substitution at nucleotide position 44, causing the glutamic acid (E) at amino acid position 15 to be replaced by a glycine (G). 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	0.058
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.090	N
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.031
Sift	Benign	0.35	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.18
MPC		0.14
ClinPred		0.0065	T
GERP RS		2.0
Varity_R		0.037
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs36005166; hg19: chr6-18399809;