5-73753111-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001177693.2(ARHGEF28):c.384A>G(p.Ala128=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,592,358 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.33

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 5-73753111-A-G is Benign according to our data. Variant chr5-73753111-A-G is described in ClinVar as [Benign]. Clinvar id is 713966.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-6.33 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF28	NM_001177693.2	c.384A>G	p.Ala128=	synonymous_variant	4/36	ENST00000513042.7
ARHGEF28	NM_001080479.3	c.384A>G	p.Ala128=	synonymous_variant	4/37
ARHGEF28	NM_001388078.1	c.384A>G	p.Ala128=	synonymous_variant	4/35
ARHGEF28	NM_001388076.1	c.181+3127A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.384A>G	p.Ala128=	synonymous_variant	4/36	5	NM_001177693.2

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00177 AC: 399 AN: 225972 Hom.: 2 AF XY: 0.00134 AC XY: 162 AN XY: 121046

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.000131

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00203

GnomAD4 exome AF: 0.000354 AC: 510 AN: 1440052 Hom.: 3 Cov.: 31 AF XY: 0.000279 AC XY: 199 AN XY: 713930

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.0000415

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.000487

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74478

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000402 Hom.: 1

Bravo AF: 0.00160

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.014
Dann	Benign	0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368285021; hg19: chr5-73048936;