11-74749099-G-C

Position:

• chr11-74749099-G-C

Variant summary

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

The NM_001098638.2(RNF169):​c.219G>C​(p.Glu73Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF169 NM_001098638.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

RNF169 (HGNC:26961): (ring finger protein 169) Enables K63-linked polyubiquitin modification-dependent protein binding activity and nucleosome binding activity. Involved in cellular response to DNA damage stimulus and negative regulation of double-strand break repair. Located in cytosol; nuclear lumen; and site of double-strand break. [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/exons	MANE	UniProt
RNF169	NM_001098638.2	c.219G>C	p.Glu73Asp	missense_variant	1/6	ENST00000299563.5
RNF169	XM_011544889.4	c.219G>C	p.Glu73Asp	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF169	ENST00000299563.5	c.219G>C	p.Glu73Asp	missense_variant	1/6	1	NM_001098638.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.219G>C (p.E73D) alteration is located in exon 1 (coding exon 1) of the RNF169 gene. This alteration results from a G to C substitution at nucleotide position 219, causing the glutamic acid (E) at amino acid position 73 to be replaced by an aspartic acid (D). 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	0.19
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	-0.60	N
MutationTaster	Benign	0.68	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.34
Sift	Benign	0.072	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.50	P
Vest4		0.38
MutPred		0.38		Gain of helix (P = 0.062);
MVP		0.90
MPC		0.73
ClinPred		0.72	D
GERP RS		3.6
Varity_R		0.093
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-74460144;