5-55220439-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001190787.3(MCIDAS):c.1085C>T(p.Ala362Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000846 in 1,536,080 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: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017221868).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000453 (69/152278) while in subpopulation AFR AF= 0.00164 (68/41556). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCIDAS	NM_001190787.3	c.1085C>T	p.Ala362Val	missense_variant	7/7	ENST00000513312.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCIDAS	ENST00000513312.3	c.1085C>T	p.Ala362Val	missense_variant	7/7	1	NM_001190787.3	P1
MCIDAS	ENST00000513468.5	c.*549C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000741 AC: 10 AN: 134922 Hom.: 0 AF XY: 0.0000681 AC XY: 5 AN XY: 73384

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000441 AC: 61 AN: 1383802 Hom.: 0 Cov.: 30 AF XY: 0.0000381 AC XY: 26 AN XY: 682842

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00

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: 0.00000371

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74460

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000472

ExAC AF: 0.0000949 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 19, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 362 of the MCIDAS protein (p.Ala362Val). This variant is present in population databases (rs539275390, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with MCIDAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 961021). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.47	P
Vest4		0.17
MutPred		0.32		Gain of sheet (P = 0.0101);
MVP		0.099
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.19
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs539275390; hg19: chr5-54516267;