5-73749681-T-C

Position:

• chr5-73749681-T-C

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.34-156T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,062 control chromosomes in the GnomAD database, including 4,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.22 (4003 hom., cov: 32)
• Consequence: ARHGEF28 NM_001177693.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.197

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-73749681-T-C is Benign according to our data. Variant chr5-73749681-T-C is described in ClinVar as [Benign]. Clinvar id is 1278356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.34-156T>C		intron_variant		ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.34-156T>C		intron_variant			NP_001073948.2
ARHGEF28	NM_001388076.1	c.34-156T>C		intron_variant			NP_001375005.1
ARHGEF28	NM_001388078.1	c.34-156T>C		intron_variant			NP_001375007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.34-156T>C		intron_variant		5	NM_001177693.2	ENSP00000441436

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33265 AN: 151944 Hom.: 4000 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.232

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.219 AC: 33271 AN: 152062 Hom.: 4003 Cov.: 32 AF XY: 0.219 AC XY: 16291 AN XY: 74332

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.230

Alfa AF: 0.254 Hom.: 4976

Bravo AF: 0.206

Asia WGS AF: 0.158 AC: 551 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.76

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: rs17552626; hg19: chr5-73045506; COSMIC: COSV55257506;