chr7-150289535-A-G

Variant names:

• chr7-150289535-A-G
• rs755774050
• NM_001164458.2:c.212T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001164458.2(ACTR3C):​c.212T>C​(p.Ile71Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,605,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACTR3C NM_001164458.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.45
• Publications: 0 publications found

Genes affected

ACTR3C (HGNC:37282): (actin related protein 3C) Predicted to enable ATP binding activity. Predicted to contribute to actin filament binding activity. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTR3C	NM_001164458.2	c.212T>C	p.Ile71Thr	missense_variant	Exon 4 of 8	ENST00000683684.1	NP_001157930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTR3C	ENST00000683684.1	c.212T>C	p.Ile71Thr	missense_variant	Exon 4 of 8		NM_001164458.2	ENSP00000507618.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151610 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233108 AF XY: 0.00000795

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000175

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1453542 Hom.: 0 Cov.: 31 AF XY: 0.00000554 AC XY: 4 AN XY: 721576

African (AFR) AF: 0.0000301 AC: 1 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 84600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60074

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74010

African (AFR) AF: 0.00 AC: 0 AN: 41102

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212T>C (p.I71T) alteration is located in exon 4 (coding exon 3) of the ACTR3C gene. This alteration results from a T to C substitution at nucleotide position 212, causing the isoleucine (I) at amino acid position 71 to be replaced by a threonine (T). 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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	.;M;.;.
PhyloP100		8.5
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.025	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;.
Polyphen		0.38	.;B;.;.
Vest4		0.93, 0.94
MutPred		0.80		.;Gain of catalytic residue at I71 (P = 0.0507);Gain of catalytic residue at I71 (P = 0.0507);.;
MVP		0.87
MPC		2.9
ClinPred		0.98	D
GERP RS		2.0
Varity_R		0.33
gMVP		0.69
Mutation Taster		=61/39	polymorphism

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: rs755774050; hg19: chr7-149986624;