Genetic Variant MICALL1:p.Ala123Thr (chr22-37917736-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033386.4(MICALL1):c.367G>A(p.Ala123Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

MICALL1
NM_033386.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00800

Variant links:

Genes affected

MICALL1 (HGNC:29804): (MICAL like 1) Enables identical protein binding activity; phosphatidic acid binding activity; and small GTPase binding activity. Involved in several processes, including plasma membrane tubulation; protein localization to endosome; and slow endocytic recycling. Located in late endosome and recycling endosome membrane. Is extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MICALL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.011732429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MICALL1	NM_033386.4 link	c.367G>A	p.Ala123Thr	missense_variant	Exon 4 of 16	ENST00000215957.10	NP_203744.1	Q8N3F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MICALL1	ENST00000215957.10 link	c.367G>A	p.Ala123Thr	missense_variant	Exon 4 of 16	1	NM_033386.4	ENSP00000215957.6		Q8N3F8

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

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:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000223

AC:

AN:

251388

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00121

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:

0.0000288

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000368

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.367G>A (p.A123T) alteration is located in exon 4 (coding exon 4) of the MICALL1 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the alanine (A) at amino acid position 123 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

Benign

0.066

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.4

DANN

Benign

0.85

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.030

Sift

Benign

0.32

T;T

Sift4G

Benign

0.078

T;T

Polyphen

0.0010

.;B

Vest4

0.079

MVP

0.66

MPC

0.21

ClinPred

0.022

GERP RS

1.7

Varity_R

0.050

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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