chr5-73794436-T-C

Variant names:

• chr5-73794436-T-C
• rs7716253
• NM_001177693.2:c.945T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):​c.945T>C​(p.Ala315Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,599,254 control chromosomes in the GnomAD database, including 235,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28349 hom., cov: 30)
  • Exomes 𝑓: 0.53 (206851 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.71
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis

  Inheritance: AD, AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-73794436-T-C is Benign according to our data. Variant chr5-73794436-T-C is described in ClinVar as Benign. ClinVar VariationId is 257379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177693.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.945T>C	p.Ala315Ala	synonymous	Exon 8 of 36	NP_001171164.1
	ARHGEF28	NM_001080479.3		c.945T>C	p.Ala315Ala	synonymous	Exon 8 of 37	NP_001073948.2
	ARHGEF28	NM_001388078.1		c.945T>C	p.Ala315Ala	synonymous	Exon 8 of 35	NP_001375007.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.945T>C	p.Ala315Ala	synonymous	Exon 8 of 36	ENSP00000441436.1
	ARHGEF28	ENST00000437974.5	TSL:1	c.945T>C	p.Ala315Ala	synonymous	Exon 7 of 36	ENSP00000411459.1
	ARHGEF28	ENST00000426542.6	TSL:1	c.945T>C	p.Ala315Ala	synonymous	Exon 7 of 35	ENSP00000412175.2

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90764 AN: 151696 Hom.: 28302 Cov.: 30

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.558

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.563

GnomAD2 exomes AF: 0.551 AC: 128889 AN: 233804 AF XY: 0.543

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.593

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.537

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.519

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.532 AC: 770203 AN: 1447438 Hom.: 206851 Cov.: 35 AF XY: 0.531 AC XY: 381695 AN XY: 719020

African (AFR) AF: 0.794 AC: 26354 AN: 33178

American (AMR) AF: 0.584 AC: 25291 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 11336 AN: 25884

East Asian (EAS) AF: 0.485 AC: 19109 AN: 39418

South Asian (SAS) AF: 0.554 AC: 46424 AN: 83848

European-Finnish (FIN) AF: 0.549 AC: 29069 AN: 52920

Middle Eastern (MID) AF: 0.495 AC: 2849 AN: 5760

European-Non Finnish (NFE) AF: 0.524 AC: 577590 AN: 1103162

Other (OTH) AF: 0.537 AC: 32181 AN: 59948

GnomAD4 genome AF: 0.599 AC: 90867 AN: 151816 Hom.: 28349 Cov.: 30 AF XY: 0.598 AC XY: 44371 AN XY: 74162

African (AFR) AF: 0.791 AC: 32755 AN: 41408

American (AMR) AF: 0.558 AC: 8518 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1516 AN: 3468

East Asian (EAS) AF: 0.520 AC: 2677 AN: 5150

South Asian (SAS) AF: 0.565 AC: 2716 AN: 4806

European-Finnish (FIN) AF: 0.550 AC: 5775 AN: 10506

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35037 AN: 67908

Other (OTH) AF: 0.566 AC: 1195 AN: 2110

Alfa AF: 0.542 Hom.: 94069

Bravo AF: 0.609

Asia WGS AF: 0.571 AC: 1986 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.044
DANN	Benign	0.26
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7716253; hg19: chr5-73090261; COSMIC: COSV55249126;