14-68979396-C-A

Variant names:

• chr14-68979396-C-A
• rs3809393
• ENST00000193403.11:c.-340G>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The ENST00000193403.11(ACTN1):​c.-340G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 174,934 control chromosomes in the GnomAD database, including 2,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2488 hom., cov: 33)
  • Exomes 𝑓: 0.16 (467 hom.)
• Consequence: ACTN1 ENST00000193403.11 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148
• Publications: 8 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-DT (HGNC:20131): (ACTN1 divergent transcript)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP6: Variant 14-68979396-C-A is Benign according to our data. Variant chr14-68979396-C-A is described in ClinVar as Benign. ClinVar VariationId is 1253662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000193403.11. 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.-340G>T		upstream_gene	N/A	NP_001123476.1	P12814-3
	ACTN1	NM_001424012.1		c.-340G>T		upstream_gene	N/A	NP_001410941.1
	ACTN1	NM_001424013.1		c.-340G>T		upstream_gene	N/A	NP_001410942.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	ENST00000193403.11	TSL:1	c.-340G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 21	ENSP00000193403.6	P12814-1
	ACTN1	ENST00000193403.11	TSL:1	c.-340G>T		5_prime_UTR	Exon 1 of 21	ENSP00000193403.6	P12814-1
	ACTN1	ENST00000938290.1		c.-66-274G>T		intron	N/A	ENSP00000608349.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25817 AN: 152036 Hom.: 2482 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.00792

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.164 AC: 3737 AN: 22782 Hom.: 467 Cov.: 0 AF XY: 0.166 AC XY: 1968 AN XY: 11890

African (AFR) AF: 0.0839 AC: 70 AN: 834

American (AMR) AF: 0.0824 AC: 42 AN: 510

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 138 AN: 924

East Asian (EAS) AF: 0.0406 AC: 61 AN: 1502

South Asian (SAS) AF: 0.148 AC: 171 AN: 1154

European-Finnish (FIN) AF: 0.134 AC: 159 AN: 1184

Middle Eastern (MID) AF: 0.108 AC: 14 AN: 130

European-Non Finnish (NFE) AF: 0.190 AC: 2847 AN: 15012

Other (OTH) AF: 0.153 AC: 235 AN: 1532

GnomAD4 genome AF: 0.170 AC: 25848 AN: 152152 Hom.: 2488 Cov.: 33 AF XY: 0.167 AC XY: 12396 AN XY: 74388

African (AFR) AF: 0.106 AC: 4394 AN: 41538

American (AMR) AF: 0.151 AC: 2317 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 666 AN: 3468

East Asian (EAS) AF: 0.00793 AC: 41 AN: 5168

South Asian (SAS) AF: 0.124 AC: 600 AN: 4830

European-Finnish (FIN) AF: 0.176 AC: 1864 AN: 10596

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.227 AC: 15414 AN: 67948

Other (OTH) AF: 0.170 AC: 358 AN: 2110

Alfa AF: 0.125 Hom.: 312

Bravo AF: 0.163

Asia WGS AF: 0.0590 AC: 204 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		0.15
PromoterAI		-0.10	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs3809393; hg19: chr14-69446113;