Genetic Variant NM_177532.5:c.863A>T (chr4-73576485-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_177532.5(RASSF6):c.863A>T(p.His288Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,428,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

RASSF6
NM_177532.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.04

Variant links:

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]

RASSF6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASSF6	NM_177532.5 link	c.863A>T	p.His288Leu	missense_variant	Exon 10 of 11	ENST00000307439.10	NP_803876.1	Q6ZTQ3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASSF6	ENST00000307439.10 link	c.863A>T	p.His288Leu	missense_variant	Exon 10 of 11	1	NM_177532.5	ENSP00000303877.5	Q6ZTQ3-2
RASSF6	ENST00000335049.5 link	c.827A>T	p.His276Leu	missense_variant	Exon 9 of 10	1		ENSP00000335582.5	Q6ZTQ3-3
RASSF6	ENST00000395777.6 link	c.761A>T	p.His254Leu	missense_variant	Exon 9 of 10	1		ENSP00000379123.2	Q6ZTQ3-4
RASSF6	ENST00000342081.7 link	c.959A>T	p.His320Leu	missense_variant	Exon 10 of 11	2		ENSP00000340578.3	Q6ZTQ3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428264

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

707724

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.14e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.959A>T (p.H320L) alteration is located in exon 10 (coding exon 10) of the RASSF6 gene. This alteration results from a A to T substitution at nucleotide position 959, causing the histidine (H) at amino acid position 320 to be replaced by a leucine (L). 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

0.32

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Benign

0.033

.;T;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

.;M;.;.

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

0.95, 0.94, 0.65

.;P;P;P

Vest4

0.58

MutPred

0.42

.;Gain of helix (P = 0.0854);.;.;

MVP

0.60

MPC

0.0082

ClinPred

0.99

GERP RS

6.1

Varity_R

0.42

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over