5-73883847-C-T

Variant names:

• chr5-73883847-C-T
• rs3749645
• NM_001177693.2:c.3018C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001177693.2(ARHGEF28):​c.3018C>T​(p.Tyr1006Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,569,962 control chromosomes in the GnomAD database, including 13,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1560 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12267 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.25

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 5-73883847-C-T is Benign according to our data. Variant chr5-73883847-C-T is described in ClinVar as [Benign]. Clinvar id is 257366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73883847-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.3018C>T	p.Tyr1006Tyr	synonymous_variant	Exon 24 of 36	ENST00000513042.7	NP_001171164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.3018C>T	p.Tyr1006Tyr	synonymous_variant	Exon 24 of 36	5	NM_001177693.2	ENSP00000441436.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20591 AN: 151828 Hom.: 1560 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.0896

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.128 AC: 24278 AN: 189534 AF XY: 0.130

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0787

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.126 AC: 178372 AN: 1418016 Hom.: 12267 Cov.: 30 AF XY: 0.126 AC XY: 88612 AN XY: 701144

African (AFR) AF: 0.168 AC: 5434 AN: 32266

American (AMR) AF: 0.0793 AC: 3094 AN: 39002

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2667 AN: 25278

East Asian (EAS) AF: 0.284 AC: 10700 AN: 37634

South Asian (SAS) AF: 0.169 AC: 13254 AN: 78638

European-Finnish (FIN) AF: 0.110 AC: 5605 AN: 51172

Middle Eastern (MID) AF: 0.172 AC: 978 AN: 5700

European-Non Finnish (NFE) AF: 0.118 AC: 129086 AN: 1089554

Other (OTH) AF: 0.129 AC: 7554 AN: 58772

GnomAD4 genome AF: 0.136 AC: 20602 AN: 151946 Hom.: 1560 Cov.: 32 AF XY: 0.136 AC XY: 10080 AN XY: 74250

African (AFR) AF: 0.170 AC: 7030 AN: 41458

American (AMR) AF: 0.0893 AC: 1364 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3470

East Asian (EAS) AF: 0.288 AC: 1482 AN: 5154

South Asian (SAS) AF: 0.181 AC: 869 AN: 4806

European-Finnish (FIN) AF: 0.105 AC: 1102 AN: 10538

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7811 AN: 67940

Other (OTH) AF: 0.136 AC: 287 AN: 2106

Alfa AF: 0.124 Hom.: 4849

Bravo AF: 0.137

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.9
DANN	Benign	0.92
PhyloP100		1.2
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3749645; hg19: chr5-73179672; COSMIC: COSV55257068; COSMIC: COSV55257068;