13-26214920-G-C

Variant names:

• chr13-26214920-G-C
• rs1183285438
• NM_005977.4:c.962C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005977.4(RNF6):​c.962C>G​(p.Thr321Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000014 (0 hom.)
• Consequence: RNF6 NM_005977.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088189304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF6	NM_005977.4	c.962C>G	p.Thr321Ser	missense_variant	Exon 5 of 5	ENST00000381588.9	NP_005968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF6	ENST00000381588.9	c.962C>G	p.Thr321Ser	missense_variant	Exon 5 of 5	1	NM_005977.4	ENSP00000371000.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.962C>G (p.T321S) alteration is located in exon 5 (coding exon 3) of the RNF6 gene. This alteration results from a C to G substitution at nucleotide position 962, causing the threonine (T) at amino acid position 321 to be replaced by a serine (S). 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	0.083
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.042	T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.47	.;.;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.19	N;N;N
REVEL	Benign	0.044
Sift	Benign	0.077	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.010	B;B;B
Vest4		0.10
MutPred		0.14		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.29
MPC		0.40
ClinPred		0.26	T
GERP RS		3.6
Varity_R		0.076
gMVP		0.26

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: rs1183285438; hg19: chr13-26789057;