5-73794436-T-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001177693.2(ARHGEF28):​c.945T>G​(p.Ala315Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A315A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.

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>G	p.Ala315Ala	synonymous	Exon 8 of 36	NP_001171164.1
	ARHGEF28	NM_001080479.3		c.945T>G	p.Ala315Ala	synonymous	Exon 8 of 37	NP_001073948.2
	ARHGEF28	NM_001388078.1		c.945T>G	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>G	p.Ala315Ala	synonymous	Exon 8 of 36	ENSP00000441436.1
	ARHGEF28	ENST00000437974.5	TSL:1	c.945T>G	p.Ala315Ala	synonymous	Exon 7 of 36	ENSP00000411459.1
	ARHGEF28	ENST00000426542.6	TSL:1	c.945T>G	p.Ala315Ala	synonymous	Exon 7 of 35	ENSP00000412175.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450018 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 720228

African (AFR) AF: 0.00 AC: 0 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 43424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 84032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105182

Other (OTH) AF: 0.0000167 AC: 1 AN: 60048

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.038
DANN	Benign	0.23
PhyloP100		-1.7

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;