chr6-109465909-G-A

Variant names:

• chr6-109465909-G-A
• rs776310741
• NM_014797.3:c.2036C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001286613.2(MICAL1):​c.-232C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,884 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MICAL1 NM_001286613.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0280
• Publications: 0 publications found

Genes affected

ZBTB24 (HGNC:21143): (zinc finger and BTB domain containing 24) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be located in nucleus. Implicated in immunodeficiency-centromeric instability-facial anomalies syndrome 2. [provided by Alliance of Genome Resources, Apr 2022]

MICAL1 (HGNC:20619): (microtubule associated monooxygenase, calponin and LIM domain containing 1) This gene encodes an enzyme that oxidizes methionine residues on actin, thereby promoting depolymerization of actin filaments. This protein interacts with and regulates signalling by NEDD9/CAS-L (neural precursor cell expressed, developmentally down-regulated 9). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

MICAL1 Gene-Disease associations (from GenCC):

• epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05614689).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286613.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB24	NM_014797.3	MANE Select	c.2036C>T	p.Pro679Leu	missense	Exon 7 of 7	NP_055612.2	O43167-1
	MICAL1	NM_001286613.2		c.-232C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	NP_001273542.1	Q8TDZ2-4
	MICAL1	NM_001286613.2		c.-232C>T		5_prime_UTR	Exon 1 of 25	NP_001273542.1	Q8TDZ2-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB24	ENST00000230122.4	TSL:1 MANE Select	c.2036C>T	p.Pro679Leu	missense	Exon 7 of 7	ENSP00000230122.4	O43167-1
	MICAL1	ENST00000630715.2	TSL:2	c.-232C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	ENSP00000486901.1	Q8TDZ2-4
	ZBTB24	ENST00000698516.1		c.2036C>T	p.Pro679Leu	missense	Exon 7 of 7	ENSP00000513766.1	O43167-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251490 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.028
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.077
Sift	Benign	0.48	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.14		Loss of glycosylation at P679 (P = 0.0032)
MVP		0.16
MPC		0.17
ClinPred		0.032	T
GERP RS		2.6
PromoterAI		0.054	Neutral
Varity_R		0.015
gMVP		0.13
Mutation Taster		=98/2	polymorphism

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: rs776310741; hg19: chr6-109787112; COSMIC: COSV105069772;