19-38731307-A-T

Variant names:

• chr19-38731307-A-T
• rs4801859
• NM_004924.6:c.*1875A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004924.6(ACTN4):​c.*1875A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,034,664 control chromosomes in the GnomAD database, including 28,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4162 hom., cov: 32)
  • Exomes 𝑓: 0.23 (24014 hom.)
• Consequence: ACTN4 NM_004924.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.68
• Publications: 4 publications found

Genes affected

ACTN4 (HGNC:166): (actinin alpha 4) 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, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

CAPN12 (HGNC:13249): (calpain 12) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes a member of the calpain large subunit family. [provided by RefSeq, Jun 2012]

CAPN12 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-38731307-A-T is Benign according to our data. Variant chr19-38731307-A-T is described in ClinVar as Benign. ClinVar VariationId is 1293783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. 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
	ACTN4	NM_004924.6	MANE Select	c.*1875A>T		3_prime_UTR	Exon 21 of 21	NP_004915.2
	CAPN12	NM_144691.4	MANE Select	c.1958-84T>A		intron	N/A	NP_653292.2	Q6ZSI9
	ACTN4	NM_001411143.1		c.*1875A>T		3_prime_UTR	Exon 21 of 21	NP_001398072.1	F5GXS2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.*1875A>T		3_prime_UTR	Exon 21 of 21	ENSP00000252699.2	O43707-1
	CAPN12	ENST00000328867.9	TSL:1 MANE Select	c.1958-84T>A		intron	N/A	ENSP00000331636.3	Q6ZSI9
	CAPN12	ENST00000593700.5	TSL:1	n.522-84T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34514 AN: 151824 Hom.: 4146 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.227 AC: 200194 AN: 882722 Hom.: 24014 Cov.: 12 AF XY: 0.233 AC XY: 107087 AN XY: 459652

African (AFR) AF: 0.244 AC: 5503 AN: 22536

American (AMR) AF: 0.245 AC: 10371 AN: 42270

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 5572 AN: 22104

East Asian (EAS) AF: 0.126 AC: 4641 AN: 36724

South Asian (SAS) AF: 0.351 AC: 25717 AN: 73244

European-Finnish (FIN) AF: 0.217 AC: 9297 AN: 42774

Middle Eastern (MID) AF: 0.352 AC: 1115 AN: 3170

European-Non Finnish (NFE) AF: 0.215 AC: 128479 AN: 598636

Other (OTH) AF: 0.230 AC: 9499 AN: 41264

GnomAD4 genome AF: 0.228 AC: 34584 AN: 151942 Hom.: 4162 Cov.: 32 AF XY: 0.230 AC XY: 17046 AN XY: 74272

African (AFR) AF: 0.233 AC: 9663 AN: 41432

American (AMR) AF: 0.240 AC: 3654 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 858 AN: 3470

East Asian (EAS) AF: 0.144 AC: 741 AN: 5152

South Asian (SAS) AF: 0.366 AC: 1760 AN: 4812

European-Finnish (FIN) AF: 0.202 AC: 2141 AN: 10578

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.217 AC: 14759 AN: 67936

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.221 Hom.: 476

Bravo AF: 0.228

Asia WGS AF: 0.333 AC: 1154 AN: 3478

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	-0.89
CADD	Benign	0.22
DANN	Benign	0.49
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs4801859; hg19: chr19-39221947; COSMIC: COSV107260283; COSMIC: COSV107260283;