rs1381740422

Variant names:

• chr14-68874964-C-G
• rs1381740422
• NM_001130004.2:c.2640G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130004.2(ACTN1):​c.2640G>C​(p.Glu880Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACTN1 NM_001130004.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.420
• Publications: 0 publications found

Genes affected

ACTN1 (HGNC:163): (actinin alpha 1) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACTN1 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3116156).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130004.2. 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
	ACTN1	NM_001130004.2	MANE Select	c.2640G>C	p.Glu880Asp	missense	Exon 22 of 22	NP_001123476.1	P12814-3
	ACTN1	NM_001424012.1		c.2703G>C	p.Glu901Asp	missense	Exon 21 of 21	NP_001410941.1
	ACTN1	NM_001424013.1		c.2700G>C	p.Glu900Asp	missense	Exon 22 of 22	NP_001410942.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	ENST00000394419.9	TSL:1 MANE Select	c.2640G>C	p.Glu880Asp	missense	Exon 22 of 22	ENSP00000377941.4	P12814-3
	ACTN1	ENST00000538545.6	TSL:1	c.2688G>C	p.Glu896Asp	missense	Exon 21 of 21	ENSP00000439828.2	P12814-4
	ACTN1	ENST00000193403.11	TSL:1	c.2574G>C	p.Glu858Asp	missense	Exon 21 of 21	ENSP00000193403.6	P12814-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250282 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461514 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.42
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.17
Sift	Benign	0.098	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.35
MutPred		0.63		Gain of catalytic residue at P853 (P = 0.001)
MVP		0.80
MPC		0.12
ClinPred		0.24	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.62
Mutation Taster		=40/60	disease causing

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: rs1381740422; hg19: chr14-69341681;