rs121434523

Variant names:

• chr13-26215158-C-T
• rs121434523
• NM_005977.4:c.724G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000381588.9(RNF6):​c.724G>A​(p.Ala242Thr) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF6 ENST00000381588.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.415
• Publications: 0 publications found

Genes affected

RNF6 (HGNC:10069): (ring finger protein 6) The protein encoded by this gene contains a RING-H2 finger motif. Deletions and mutations in this gene were detected in esophageal squamous cell carcinoma (ESCC), suggesting that this protein may be a potential tumor suppressor. Studies of the mouse counterpart suggested a role of this protein in the transcription regulation that controls germinal differentiation. Multiple alternatively spliced transcript variants encoding the same protein are observed. [provided by RefSeq, Jul 2008]

RNF6 Gene-Disease associations (from GenCC):

• esophageal cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-26215158-C-T is Pathogenic according to our data. Variant chr13-26215158-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5701.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05306527). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381588.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF6	NM_005977.4	MANE Select	c.724G>A	p.Ala242Thr	missense	Exon 5 of 5	NP_005968.1
	RNF6	NM_183043.3		c.724G>A	p.Ala242Thr	missense	Exon 5 of 5	NP_898864.1
	RNF6	NM_183044.3		c.724G>A	p.Ala242Thr	missense	Exon 5 of 5	NP_898865.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF6	ENST00000381588.9	TSL:1 MANE Select	c.724G>A	p.Ala242Thr	missense	Exon 5 of 5	ENSP00000371000.4
	RNF6	ENST00000346166.7	TSL:1	c.724G>A	p.Ala242Thr	missense	Exon 5 of 5	ENSP00000342121.3
	RNF6	ENST00000381570.7	TSL:1	c.724G>A	p.Ala242Thr	missense	Exon 5 of 5	ENSP00000370982.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Esophageal squamous cell carcinoma, somatic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.87
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.99	L
PhyloP100		-0.41
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.096
Sift	Benign	0.13	T
Sift4G	Benign	0.67	T
Polyphen		0.0010	B
Vest4		0.059
MutPred		0.23		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.16
MPC		0.29
ClinPred		0.040	T
GERP RS		0.90
Varity_R		0.044
gMVP		0.29
Mutation Taster		=18/82	disease causing (ClinVar)

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: rs121434523; hg19: chr13-26789295;