22-17872017-T-G

Variant names:

• chr22-17872017-T-G
• rs5992128
• NM_015241.3:c.2248A>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015241.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICAL3	NM_015241.3	MANE Select	c.2248A>C	p.Met750Leu	missense	Exon 17 of 32	NP_056056.2
	MICAL3	NM_001136004.3		c.2620A>C	p.Met874Leu	missense	Exon 20 of 22	NP_001129476.1
	MICAL3	NM_001122731.2		c.2248A>C	p.Met750Leu	missense	Exon 16 of 20	NP_001116203.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICAL3	ENST00000441493.7	TSL:5 MANE Select	c.2248A>C	p.Met750Leu	missense	Exon 17 of 32	ENSP00000416015.2
	MICAL3	ENST00000585038.1	TSL:1	c.2620A>C	p.Met874Leu	missense	Exon 20 of 22	ENSP00000462033.1
	MICAL3	ENST00000400561.6	TSL:1	c.2248A>C	p.Met750Leu	missense	Exon 16 of 20	ENSP00000383406.2

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

GnomAD2 exomes AF: 0.0194 AC: 4373 AN: 225502 AF XY: 0.0189

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 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

African (AFR) AF: 0.0370 AC: 1229 AN: 33256

American (AMR) AF: 0.0138 AC: 596 AN: 43178

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 681 AN: 25866

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39316

South Asian (SAS) AF: 0.00283 AC: 237 AN: 83760

European-Finnish (FIN) AF: 0.0186 AC: 969 AN: 52040

Middle Eastern (MID) AF: 0.0346 AC: 199 AN: 5758

European-Non Finnish (NFE) AF: 0.0246 AC: 27252 AN: 1106610

Other (OTH) AF: 0.0206 AC: 1239 AN: 60004

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

African (AFR) AF: 0.0342 AC: 1420 AN: 41572

American (AMR) AF: 0.0238 AC: 365 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10626

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0237 AC: 1615 AN: 68012

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0253 Hom.: 133

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 v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.87
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.072
MutPred		0.31		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
Mutation Taster		=99/1	polymorphism (auto)

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: rs5992128; hg19: chr22-18354783;