rs5992128

chr22-17872017-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_015241.3(MICAL3):c.2248A>C(p.Met750Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,602,090 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (62 hom., cov: 33)
  • Exomes 𝑓: 0.022 (397 hom.)
• Consequence: MICAL3 NM_015241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.871

Genes affected

MICAL3 (HGNC:24694): (microtubule associated monooxygenase, calponin and LIM domain containing 3) Enables actin binding activity. Involved in actin filament depolymerization. Located in several cellular components, including Flemming body; intercellular bridge; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016676784).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.025 (3809/152302) while in subpopulation AFR AF= 0.0342 (1420/41572). AF 95% confidence interval is 0.0327. There are 62 homozygotes in gnomad4. There are 1844 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICAL3	NM_015241.3	c.2248A>C	p.Met750Leu	missense_variant	17/32	ENST00000441493.7
MICAL3	NM_001136004.3	c.2620A>C	p.Met874Leu	missense_variant	20/22
MICAL3	NM_001122731.2	c.2248A>C	p.Met750Leu	missense_variant	16/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICAL3	ENST00000441493.7	c.2248A>C	p.Met750Leu	missense_variant	17/32	5	NM_015241.3	P1

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3799 AN: 152184 Hom.: 60 Cov.: 33

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0194 AC: 4373 AN: 225502 Hom.: 47 AF XY: 0.0189 AC XY: 2308 AN XY: 122416

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0134

Gnomad ASJ exome AF: 0.0248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00299

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0265

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0224 AC: 32403 AN: 1449788 Hom.: 397 Cov.: 32 AF XY: 0.0218 AC XY: 15697 AN XY: 719908

Gnomad4 AFR exome AF: 0.0370

Gnomad4 AMR exome AF: 0.0138

Gnomad4 ASJ exome AF: 0.0263

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.0186

Gnomad4 NFE exome AF: 0.0246

Gnomad4 OTH exome AF: 0.0206

GnomAD4 genome AF: 0.0250 AC: 3809 AN: 152302 Hom.: 62 Cov.: 33 AF XY: 0.0248 AC XY: 1844 AN XY: 74458

Gnomad4 AFR AF: 0.0342

Gnomad4 AMR AF: 0.0238

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0252 Hom.: 95

Bravo AF: 0.0255

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0231 AC: 89

ESP6500AA AF: 0.0344 AC: 108

ESP6500EA AF: 0.0251 AC: 180

ExAC AF: 0.0192 AC: 2312

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Benign	0.67
DEOGEN2	Benign	0.0020	T;.;.;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.65	T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N;N;N;N;.
REVEL	Benign	0.051
Sift	Benign	1.0	T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;B;.
Vest4		0.072
MutPred		0.31		Loss of MoRF binding (P = 0.1041);Loss of MoRF binding (P = 0.1041);.;Loss of MoRF binding (P = 0.1041);.;
MPC		0.13
ClinPred		0.0098	T
GERP RS		2.3
Varity_R		0.061
gMVP		0.10

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: rs5992128; hg19: chr22-18354783;