rs191563093

Variant names:

• chr5-73753042-G-T
• rs191563093
• NM_001177693.2:c.315G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-73753042-G-T
• chr5-73753042-G-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001177693.2(ARHGEF28):​c.315G>T​(p.Thr105Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,609,856 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (61 hom.)
• Consequence: ARHGEF28 NM_001177693.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0300
• Publications: 1 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, SD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-73753042-G-T is Benign according to our data. Variant chr5-73753042-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	NM_001177693.2	MANE Select	c.315G>T	p.Thr105Thr	synonymous	Exon 4 of 36	NP_001171164.1	Q8N1W1-1
	ARHGEF28	NM_001080479.3		c.315G>T	p.Thr105Thr	synonymous	Exon 4 of 37	NP_001073948.2	Q8N1W1-6
	ARHGEF28	NM_001388078.1		c.315G>T	p.Thr105Thr	synonymous	Exon 4 of 35	NP_001375007.1	Q8N1W1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF28	ENST00000513042.7	TSL:5 MANE Select	c.315G>T	p.Thr105Thr	synonymous	Exon 4 of 36	ENSP00000441436.1	Q8N1W1-1
	ARHGEF28	ENST00000437974.5	TSL:1	c.315G>T	p.Thr105Thr	synonymous	Exon 3 of 36	ENSP00000411459.1	Q8N1W1-6
	ARHGEF28	ENST00000426542.6	TSL:1	c.315G>T	p.Thr105Thr	synonymous	Exon 3 of 35	ENSP00000412175.2	Q8N1W1-1

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 531 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00667

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00335 AC: 804 AN: 239938 AF XY: 0.00342

Gnomad AFR exome AF: 0.000903

Gnomad AMR exome AF: 0.000986

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000954

Gnomad NFE exome AF: 0.00663

Gnomad OTH exome AF: 0.00307

GnomAD4 exome AF: 0.00624 AC: 9091 AN: 1457568 Hom.: 61 Cov.: 31 AF XY: 0.00594 AC XY: 4302 AN XY: 724664

African (AFR) AF: 0.000988 AC: 33 AN: 33386

American (AMR) AF: 0.000930 AC: 41 AN: 44064

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.0000820 AC: 7 AN: 85396

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 53036

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5754

European-Non Finnish (NFE) AF: 0.00772 AC: 8571 AN: 1110152

Other (OTH) AF: 0.00608 AC: 366 AN: 60224

GnomAD4 genome AF: 0.00349 AC: 532 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00303 AC XY: 226 AN XY: 74468

African (AFR) AF: 0.000866 AC: 36 AN: 41558

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00668 AC: 454 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00352

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.8
DANN	Benign	0.44
PhyloP100		0.030
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs191563093; hg19: chr5-73048867;