5-73911547-T-A

Position:

• chr5-73911547-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001177693.2(ARHGEF28):​c.4920T>A​(p.His1640Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,607,754 control chromosomes in the GnomAD database, including 114,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (10389 hom., cov: 32)
  • Exomes 𝑓: 0.37 (104078 hom.)
• Consequence: ARHGEF28 NM_001177693.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.484

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.567172E-4).
• BP6: Variant 5-73911547-T-A is Benign according to our data. Variant chr5-73911547-T-A is described in ClinVar as [Benign]. Clinvar id is 257374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73911547-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.4920T>A	p.His1640Gln	missense_variant	35/36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.4920T>A	p.His1640Gln	missense_variant	35/36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55546 AN: 151978 Hom.: 10373 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.343

GnomAD3 exomes AF: 0.330 AC: 79122 AN: 240052 Hom.: 14045 AF XY: 0.331 AC XY: 42960 AN XY: 129850

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.480

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.211

Gnomad FIN exome AF: 0.342

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.372 AC: 541640 AN: 1455656 Hom.: 104078 Cov.: 42 AF XY: 0.368 AC XY: 266181 AN XY: 723240

Gnomad4 AFR exome AF: 0.372

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.481

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.397

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.365 AC: 55590 AN: 152098 Hom.: 10389 Cov.: 32 AF XY: 0.358 AC XY: 26620 AN XY: 74356

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.474

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.343

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.346

Alfa AF: 0.394 Hom.: 9232

Bravo AF: 0.363

TwinsUK AF: 0.398 AC: 1476

ALSPAC AF: 0.397 AC: 1531

ESP6500AA AF: 0.359 AC: 1490

ESP6500EA AF: 0.398 AC: 3351

ExAC AF: 0.331 AC: 40010

Asia WGS AF: 0.242 AC: 843 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.10
DANN	Benign	0.48
DEOGEN2	Benign	0.0027	.;.;T;.;T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.56	T;T;T;.;.;T;T
MetaRNN	Benign	0.00026	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L;L;L;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.49	N;N;N;N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.58	T;T;T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T
Polyphen		0.0030	B;.;B;.;B;.;B
Vest4		0.12
MutPred		0.045		Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);Gain of phosphorylation at S1642 (P = 0.2469);.;.;
MPC		0.071
ClinPred		0.0012	T
GERP RS		-1.8
Varity_R		0.027
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs1478453; hg19: chr5-73207372; COSMIC: COSV55269622;