chr12-26065230-G-A

Position:

• chr12-26065230-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001394098.1(RASSF8):​c.836G>A​(p.Arg279Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,114 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: RASSF8 NM_001394098.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.49

Genes affected

RASSF8 (HGNC:13232): (Ras association domain family member 8) This gene encodes a member of the Ras-assocation domain family (RASSF) of tumor suppressor proteins. This gene is essential for maintaining adherens junction function in epithelial cells and has a role in epithelial cell migration. It is a lung tumor suppressor gene candidate. A chromosomal translocation t(12;22)(p11.2;q13.3) leading to the fusion of this gene and the FBLN1 gene is found in a complex type of synpolydactyly. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034734607).
• BP6: Variant 12-26065230-G-A is Benign according to our data. Variant chr12-26065230-G-A is described in ClinVar as [Benign]. Clinvar id is 731240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00135 (206/152252) while in subpopulation EAS AF= 0.0232 (120/5182). AF 95% confidence interval is 0.0198. There are 2 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASSF8	NM_001394098.1	c.836G>A	p.Arg279Gln	missense_variant	4/6	ENST00000689635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASSF8	ENST00000689635.1	c.836G>A	p.Arg279Gln	missense_variant	4/6		NM_001394098.1	P1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0231

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00252 AC: 634 AN: 251288 Hom.: 7 AF XY: 0.00252 AC XY: 342 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0233

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000999 AC: 1460 AN: 1461862 Hom.: 14 Cov.: 31 AF XY: 0.00101 AC XY: 737 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0211

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00584

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.00105

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	.;T;.;T;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;.;.;.;T;.
MetaRNN	Benign	0.0035	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.42	N;N;N;N;N;N
MutationTaster	Benign	0.97	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N;N;.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.18	T;T;.;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		0.014	B;B;B;B;B;B
Vest4		0.14
MVP		0.41
MPC		0.20
ClinPred		0.13	T
GERP RS		4.2
Varity_R		0.065
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76879660; hg19: chr12-26218163; COSMIC: COSV51455176; COSMIC: COSV51455176;