1-17823036-C-T

Variant names:

• chr1-17823036-C-T
• NM_030812.3:c.28C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030812.3(ACTL8):​c.28C>T​(p.His10Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTL8 NM_030812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

Genes affected

ACTL8 (HGNC:24018): (actin like 8) Involved in epithelial cell differentiation. Predicted to be located in cytoplasm. Predicted to be part of dynactin complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTL8	NM_030812.3	c.28C>T	p.His10Tyr	missense_variant	Exon 2 of 3	ENST00000375406.2	NP_110439.2
ACTL8	XM_011542212.3	c.28C>T	p.His10Tyr	missense_variant	Exon 2 of 3		XP_011540514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTL8	ENST00000375406.2	c.28C>T	p.His10Tyr	missense_variant	Exon 2 of 3	1	NM_030812.3	ENSP00000364555.1
ACTL8	ENST00000617065.1	c.28C>T	p.His10Tyr	missense_variant	Exon 1 of 2	2		ENSP00000481590.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28C>T (p.H10Y) alteration is located in exon 1 (coding exon 1) of the ACTL8 gene. This alteration results from a C to T substitution at nucleotide position 28, causing the histidine (H) at amino acid position 10 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.67	.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.26	T;T
Polyphen		1.0	D;D
Vest4		0.40
MutPred		0.79		Loss of disorder (P = 0.0335);Loss of disorder (P = 0.0335);
MVP		0.97
MPC		1.2
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.40
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-18149531;