chr12-121780955-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_019034.3(RHOF):​c.388G>T​(p.Gly130Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G130R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RHOF
NM_019034.3 missense

Scores

10
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
RHOF (HGNC:15703): (ras homolog family member F, filopodia associated) Predicted to enable GTP binding activity; GTPase activity; and protein kinase binding activity. Involved in actin filament organization. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]
TMEM120B (HGNC:32008): (transmembrane protein 120B) Predicted to be involved in fat cell differentiation and protein heterooligomerization. Predicted to be integral component of membrane. Predicted to be active in nuclear inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RHOFNM_019034.3 linkc.388G>T p.Gly130Cys missense_variant Exon 4 of 5 ENST00000267205.7 NP_061907.2 Q9HBH0-1
TMEM120BNM_001080825.2 linkc.*5233C>A 3_prime_UTR_variant Exon 12 of 12 ENST00000449592.7 NP_001074294.2 A0PK00

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RHOFENST00000267205.7 linkc.388G>T p.Gly130Cys missense_variant Exon 4 of 5 1 NM_019034.3 ENSP00000267205.2 Q9HBH0-1
TMEM120BENST00000449592.7 linkc.*5233C>A 3_prime_UTR_variant Exon 12 of 12 1 NM_001080825.2 ENSP00000404991.2 A0PK00

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461802
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727202
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;D;D;.;T
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
D;D;D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
3.4
M;.;.;M;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-8.4
D;.;.;.;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0040
D;.;.;.;.
Sift4G
Uncertain
0.028
D;D;.;D;.
Polyphen
1.0
D;.;.;D;.
Vest4
0.96
MutPred
0.73
Gain of catalytic residue at L128 (P = 0.0021);.;.;Gain of catalytic residue at L128 (P = 0.0021);.;
MVP
0.93
MPC
0.94
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.78
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122218861; API