14-24065005-C-T

Variant names:

• chr14-24065005-C-T
• rs1393152505
• NM_138360.4:c.3128C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138360.4(CARMIL3):​c.3128C>T​(p.Pro1043Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CARMIL3 NM_138360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARMIL3	NM_138360.4	c.3128C>T	p.Pro1043Leu	missense_variant	Exon 33 of 40	ENST00000342740.6	NP_612369.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARMIL3	ENST00000342740.6	c.3128C>T	p.Pro1043Leu	missense_variant	Exon 33 of 40	5	NM_138360.4	ENSP00000340467.5
CARMIL3	ENST00000560349.1	n.1482C>T		non_coding_transcript_exon_variant	Exon 5 of 11	1
CARMIL3	ENST00000559694.5	n.2658C>T		non_coding_transcript_exon_variant	Exon 18 of 24	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459878 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3128C>T (p.P1043L) 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 3128, causing the proline (P) at amino acid position 1043 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	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.60	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.11
Sift	Uncertain	0.020	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.32		Gain of catalytic residue at P1043 (P = 0.0235);
MVP		0.43
MPC		0.35
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.16
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs1393152505; hg19: chr14-24534214; COSMIC: COSV57725332; COSMIC: COSV57725332;