Genetic Variant CARMIL3:p.Pro1085Leu (chr14-24065131-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138360.4(CARMIL3):c.3254C>T(p.Pro1085Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,459,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CARMIL3
NM_138360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Variant links:

Genes affected

CARMIL3 (HGNC:20272): (capping protein regulator and myosin 1 linker 3) Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CARMIL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16698736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARMIL3	NM_138360.4 link	c.3254C>T	p.Pro1085Leu	missense_variant	Exon 33 of 40	ENST00000342740.6	NP_612369.3	Q8ND23-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CARMIL3	ENST00000342740.6 link	c.3254C>T	p.Pro1085Leu	missense_variant	Exon 33 of 40	5	NM_138360.4	ENSP00000340467.5	Q8ND23-1
CARMIL3	ENST00000560349.1 link	n.1608C>T		non_coding_transcript_exon_variant	Exon 5 of 11	1
CARMIL3	ENST00000559694.5 link	n.2784C>T		non_coding_transcript_exon_variant	Exon 18 of 24	5

Frequencies

GnomAD3 genomes

AF:

0.0000864

AC:

AN:

150384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000981

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:

0.000134

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000137

AC:

AN:

73092

Hom.:

AF XY:

0.00

AC XY:

AN XY:

38372

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000401

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000166

AC:

218

AN:

1309578

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

638914

show subpopulations

Gnomad4 AFR exome

AF:

0.0000712

Gnomad4 AMR exome

AF:

0.0000904

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:

0.000202

Gnomad4 OTH exome

AF:

0.0000742

GnomAD4 genome

AF:

0.0000864

AC:

AN:

150384

Hom.:

Cov.:

AF XY:

0.0000681

AC XY:

AN XY:

73454

show subpopulations

Gnomad4 AFR

AF:

0.0000981

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000134

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000245

Hom.:

ExAC

AF:

0.0000206

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3254C>T (p.P1085L) alteration is located in exon 33 (coding exon 33) of the CARMIL3 gene. This alteration results from a C to T substitution at nucleotide position 3254, causing the proline (P) at amino acid position 1085 to be replaced by a leucine (L). 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

Benign

0.089

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.021

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.52

FATHMM_MKL

Uncertain

0.88

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.3

REVEL

Benign

0.098

Sift

Uncertain

0.0050

Sift4G

Benign

0.12

Polyphen

0.028

Vest4

0.39

MVP

0.15

MPC

0.32

ClinPred

0.17

GERP RS

2.0

Varity_R

0.070

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over