Genetic Variant NM_001177693.2:c.16A>C (chr5-73684867-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001177693.2(ARHGEF28):c.16A>C(p.Ser6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ARHGEF28
NM_001177693.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

ARHGEF28 (HGNC:30322): (Rho guanine nucleotide exchange factor 28) This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ARHGEF28 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.068647355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2 link	c.16A>C	p.Ser6Arg	missense_variant	Exon 2 of 36	ENST00000513042.7	NP_001171164.1	Q8N1W1-1
ARHGEF28	NM_001080479.3 link	c.16A>C	p.Ser6Arg	missense_variant	Exon 2 of 37		NP_001073948.2	Q8N1W1-6
ARHGEF28	NM_001388078.1 link	c.16A>C	p.Ser6Arg	missense_variant	Exon 2 of 35		NP_001375007.1
ARHGEF28	NM_001388076.1 link	c.16A>C	p.Ser6Arg	missense_variant	Exon 2 of 35		NP_001375005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7 link	c.16A>C	p.Ser6Arg	missense_variant	Exon 2 of 36	5	NM_001177693.2	ENSP00000441436.1		Q8N1W1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

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

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16A>C (p.S6R) alteration is located in exon 2 (coding exon 1) of the ARHGEF28 gene. This alteration results from a A to C substitution at nucleotide position 16, causing the serine (S) at amino acid position 6 to be replaced by an arginine (R). 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

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0038

.;.;T;.;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.010

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.52

T;T;T;T;.;.

M_CAP

Benign

0.0061

MetaRNN

Benign

0.069

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L;L;.;L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.23

N;N;N;N;N;N

REVEL

Benign

0.067

Sift

Uncertain

0.029

D;D;D;T;D;D

Sift4G

Benign

0.26

T;T;T;T;T;T

Polyphen

0.0090

B;.;B;.;.;B

Vest4

0.18

MutPred

0.13

Loss of disorder (P = 0.0785);Loss of disorder (P = 0.0785);Loss of disorder (P = 0.0785);Loss of disorder (P = 0.0785);Loss of disorder (P = 0.0785);Loss of disorder (P = 0.0785);

MVP

0.22

MPC

0.078

ClinPred

0.14

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.097

gMVP

0.19

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

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