4-73587889-C-A

Variant names:

• chr4-73587889-C-A
• rs1459398918
• NM_177532.5:c.333G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_177532.5(RASSF6):​c.333G>T​(p.Glu111Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RASSF6 NM_177532.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.36
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045229882).
• BP6: Variant 4-73587889-C-A is Benign according to our data. Variant chr4-73587889-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3430777.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.333G>T	p.Glu111Asp	missense	Exon 5 of 11	NP_803876.1	Q6ZTQ3-2
	RASSF6	NM_201431.2		c.429G>T	p.Glu143Asp	missense	Exon 5 of 11	NP_958834.1	Q6ZTQ3-1
	RASSF6	NM_001270392.1		c.297G>T	p.Glu99Asp	missense	Exon 4 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.333G>T	p.Glu111Asp	missense	Exon 5 of 11	ENSP00000303877.5	Q6ZTQ3-2
	RASSF6	ENST00000335049.5	TSL:1	c.297G>T	p.Glu99Asp	missense	Exon 4 of 10	ENSP00000335582.5	Q6ZTQ3-3
	RASSF6	ENST00000395777.6	TSL:1	c.333G>T	p.Glu111Asp	missense	Exon 5 of 10	ENSP00000379123.2	Q6ZTQ3-4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151928 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458326 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 725548

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.00 AC: 0 AN: 85994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109474

Other (OTH) AF: 0.0000166 AC: 1 AN: 60176

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151928 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74202

African (AFR) AF: 0.0000242 AC: 1 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 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	0.079
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L
PhyloP100		-1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.044
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.073	B
Vest4		0.14
MutPred		0.18		Gain of glycosylation at Y139 (P = 7e-04)
MVP		0.21
MPC		0.0050
ClinPred		0.14	T
GERP RS		-0.72
Varity_R		0.057
gMVP		0.26
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1459398918; hg19: chr4-74453606;