NM_177532.5:c.613G>A

Variant names:

• chr4-73582245-C-T
• rs1229836062
• NM_177532.5:c.613G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_177532.5(RASSF6):​c.613G>A​(p.Val205Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,597,676 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RASSF6 NM_177532.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.601
• Publications: 0 publications found

Genes affected

RASSF6 (HGNC:20796): (Ras association domain family member 6) This gene encodes a member of the Ras-association domain family (RASSF). Members of this family form the core of a highly conserved tumor suppressor network, the Salvador-Warts-Hippo (SWH) pathway. The protein encoded by this gene is a Ras effector protein that induces apoptosis. A genomic region containing this gene has been linked to susceptibility to viral bronchiolitis. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07194772).
• BP6: Variant 4-73582245-C-T is Benign according to our data. Variant chr4-73582245-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3312985.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177532.5. 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
	RASSF6	NM_177532.5	MANE Select	c.613G>A	p.Val205Ile	missense	Exon 7 of 11	NP_803876.1	Q6ZTQ3-2
	RASSF6	NM_201431.2		c.709G>A	p.Val237Ile	missense	Exon 7 of 11	NP_958834.1	Q6ZTQ3-1
	RASSF6	NM_001270392.1		c.577G>A	p.Val193Ile	missense	Exon 6 of 10	NP_001257321.1	Q6ZTQ3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASSF6	ENST00000307439.10	TSL:1 MANE Select	c.613G>A	p.Val205Ile	missense	Exon 7 of 11	ENSP00000303877.5	Q6ZTQ3-2
	RASSF6	ENST00000335049.5	TSL:1	c.577G>A	p.Val193Ile	missense	Exon 6 of 10	ENSP00000335582.5	Q6ZTQ3-3
	RASSF6	ENST00000395777.6	TSL:1	c.568-377G>A		intron	N/A	ENSP00000379123.2	Q6ZTQ3-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241820 AF XY: 0.00000765

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445668 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 718892

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000604 AC: 2 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 43856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25712

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.00 AC: 0 AN: 83810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102084

Other (OTH) AF: 0.00 AC: 0 AN: 59510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74262

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.2
DANN	Benign	0.38
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.60
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.10
MPC		0.0050
ClinPred		0.018	T
GERP RS		0.51
Varity_R		0.035
gMVP		0.17
Mutation Taster		=88/12	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: rs1229836062; hg19: chr4-74447962;