NM_005721.5:c.45G>T

Variant names:

• chr2-113913172-G-T
• rs1679339765
• NM_005721.5:c.45G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_005721.5(ACTR3):​c.45G>T​(p.Gly15Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,413,974 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ACTR3 NM_005721.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.1527
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 0 publications found

Genes affected

ACTR3 (HGNC:170): (actin related protein 3) The specific function of this gene has not yet been determined; however, the protein it encodes is known to be a major constituent of the ARP2/3 complex. This complex is located at the cell surface and is essential to cell shape and motility through lamellipodial actin assembly and protrusion. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Mar 2013]

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=-0.33).
• BP6: Variant 2-113913172-G-T is Benign according to our data. Variant chr2-113913172-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3142426.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.26 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005721.5. 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
	ACTR3	NM_005721.5	MANE Select	c.45G>T	p.Gly15Gly	splice_region synonymous	Exon 2 of 12	NP_005712.1	P61158
	ACTR3	NM_001277140.1		c.-109G>T		splice_region	Exon 2 of 12	NP_001264069.1	B4DXW1
	ACTR3	NM_001277140.1		c.-109G>T		5_prime_UTR	Exon 2 of 12	NP_001264069.1	B4DXW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTR3	ENST00000263238.7	TSL:1 MANE Select	c.45G>T	p.Gly15Gly	splice_region synonymous	Exon 2 of 12	ENSP00000263238.2	P61158
	ACTR3	ENST00000535589.3	TSL:2	c.-109G>T		splice_region	Exon 2 of 12	ENSP00000444987.1	B4DXW1
	ACTR3	ENST00000868069.1		c.45G>T	p.Gly15Gly	splice_region synonymous	Exon 3 of 13	ENSP00000538128.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000283 AC: 4 AN: 1413974 Hom.: 0 Cov.: 26 AF XY: 0.00000284 AC XY: 2 AN XY: 704318

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31578

American (AMR) AF: 0.00 AC: 0 AN: 38978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25342

East Asian (EAS) AF: 0.00 AC: 0 AN: 38124

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 80072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1082488

Other (OTH) AF: 0.00 AC: 0 AN: 58638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000012246), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.67
PhyloP100		1.3
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.41
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: rs1679339765; hg19: chr2-114670749;