rs387907346

Positions:

• chr14-68978963-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_001130004.2(ACTN1):​c.94C>A​(p.Gln32Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACTN1 NM_001130004.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.60

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN1. . Gene score misZ 3.3621 (greater than the threshold 3.09). Trascript score misZ 5.1933 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.
• PP5: Variant 14-68978963-G-T is Pathogenic according to our data. Variant chr14-68978963-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 42029.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN1	NM_001130004.2	c.94C>A	p.Gln32Lys	missense_variant	1/22	ENST00000394419.9	NP_001123476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9	c.94C>A	p.Gln32Lys	missense_variant	1/22	1	NM_001130004.2	ENSP00000377941.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Platelet-type bleeding disorder 15 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 07, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.8	L;L;L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;D
Polyphen		0.73	P;.;P;.
Vest4		0.51
MutPred		0.54		Gain of catalytic residue at Q33 (P = 0.0135);Gain of catalytic residue at Q33 (P = 0.0135);Gain of catalytic residue at Q33 (P = 0.0135);Gain of catalytic residue at Q33 (P = 0.0135);
MVP		0.87
MPC		1.8
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.94
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs387907346; hg19: chr14-69445680;