6-127287551-T-A

Variant names:

• chr6-127287551-T-A
• rs749164556
• NM_001242850.2:c.938T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242850.2(RNF146):​c.938T>A​(p.Leu313His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L313R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RNF146 NM_001242850.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 publications found

Genes affected

RNF146 (HGNC:21336): (ring finger protein 146) Enables poly-ADP-D-ribose binding activity and ubiquitin-protein transferase activity. Involved in positive regulation of canonical Wnt signaling pathway; protein ubiquitination; and ubiquitin-dependent protein catabolic process. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07895133).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242850.2. 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
	RNF146	NM_001242850.2	MANE Select	c.938T>A	p.Leu313His	missense	Exon 3 of 3	NP_001229779.1	Q9NTX7-1
	RNF146	NM_001242849.2		c.938T>A	p.Leu313His	missense	Exon 3 of 3	NP_001229778.1	Q9NTX7-1
	RNF146	NM_001242851.1		c.938T>A	p.Leu313His	missense	Exon 3 of 3	NP_001229780.1	Q9NTX7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF146	ENST00000368314.6	TSL:2 MANE Select	c.938T>A	p.Leu313His	missense	Exon 3 of 3	ENSP00000357297.1	Q9NTX7-1
	RNF146	ENST00000610153.1	TSL:2	c.938T>A	p.Leu313His	missense	Exon 3 of 3	ENSP00000476814.1	Q9NTX7-1
	RNF146	ENST00000911117.1		c.938T>A	p.Leu313His	missense	Exon 3 of 3	ENSP00000581176.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.048
Sift	Benign	0.25	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.25		Loss of stability (P = 0.0049)
MVP		0.14
MPC		0.55
ClinPred		0.14	T
GERP RS		1.3
Varity_R		0.067
gMVP		0.17
Mutation Taster		=95/5	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: rs749164556; hg19: chr6-127608696;