chr5-73795324-C-T

Position:

• chr5-73795324-C-T

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.964-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,612,788 control chromosomes in the GnomAD database, including 14,150 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5359 hom., cov: 32)
  • Exomes 𝑓: 0.075 (8791 hom.)
• Consequence: ARHGEF28 NM_001177693.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003687
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.691

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=-0.9).
• BP6: Variant 5-73795324-C-T is Benign according to our data. Variant chr5-73795324-C-T is described in ClinVar as [Benign]. Clinvar id is 257380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-73795324-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF28	NM_001177693.2	c.964-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000513042.7	NP_001171164.1
ARHGEF28	NM_001080479.3	c.964-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001073948.2
ARHGEF28	NM_001388076.1	c.670-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001375005.1
ARHGEF28	NM_001388078.1	c.964-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001375007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF28	ENST00000513042.7	c.964-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001177693.2	ENSP00000441436

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28698 AN: 151998 Hom.: 5343 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0490

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.122 AC: 30264 AN: 248858 Hom.: 3587 AF XY: 0.113 AC XY: 15321 AN XY: 135032

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.255

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.0573

Gnomad NFE exome AF: 0.0478

Gnomad OTH exome AF: 0.0894

GnomAD4 exome AF: 0.0746 AC: 109025 AN: 1460672 Hom.: 8791 Cov.: 34 AF XY: 0.0753 AC XY: 54730 AN XY: 726672

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.0400

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.0552

Gnomad4 NFE exome AF: 0.0471

Gnomad4 OTH exome AF: 0.0987

GnomAD4 genome AF: 0.189 AC: 28765 AN: 152116 Hom.: 5359 Cov.: 32 AF XY: 0.189 AC XY: 14062 AN XY: 74392

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.0563

Gnomad4 NFE AF: 0.0490

Gnomad4 OTH AF: 0.159

Alfa AF: 0.106 Hom.: 1062

Bravo AF: 0.210

Asia WGS AF: 0.258 AC: 896 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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	Genome Diagnostics Laboratory, Amsterdam University 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
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: rs73118524; hg19: chr5-73091149; COSMIC: COSV55247714;