5-55220448-C-A

Variant names:

• chr5-55220448-C-A
• rs1561114448
• NM_001190787.3:c.1076G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001190787.3(MCIDAS):​c.1076G>T​(p.Arg359Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000145 in 1,383,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64
• Publications: 0 publications found

Genes affected

MCIDAS (HGNC:40050): (multiciliate differentiation and DNA synthesis associated cell cycle protein) This gene encodes a member of the geminin family of proteins. The encoded nuclear protein is required for the generation of multiciliated cells in respiratory epithelium. Mutations in this gene cause a rare mucociliary clearance disorder associated with recurring respiratory infections in human patients, known as reduced generation of multiple motile cilia (RGMC). [provided by RefSeq, Sep 2016]

MCIDAS Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 42

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190787.3. 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
	MCIDAS	NM_001190787.3	MANE Select	c.1076G>T	p.Arg359Leu	missense	Exon 7 of 7	NP_001177716.1	D6RGH6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCIDAS	ENST00000513312.3	TSL:1 MANE Select	c.1076G>T	p.Arg359Leu	missense	Exon 7 of 7	ENSP00000426359.1	D6RGH6
	MCIDAS	ENST00000513468.5	TSL:5	n.*540G>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422165.1	I6L8E2
	MCIDAS	ENST00000513468.5	TSL:5	n.*540G>T		3_prime_UTR	Exon 7 of 7	ENSP00000422165.1	I6L8E2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383790 Hom.: 0 Cov.: 30 AF XY: 0.00000293 AC XY: 2 AN XY: 682840

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078886

Other (OTH) AF: 0.00 AC: 0 AN: 57898

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.55		Gain of sheet (P = 0.0221)
MVP		0.43
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.31
gMVP		0.82
Mutation Taster		=71/29	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: rs1561114448; hg19: chr5-54516276;