5-55220484-G-A

Variant names:

• chr5-55220484-G-A
• rs561481156
• NM_001190787.3:c.1040C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

The NM_001190787.3(MCIDAS):​c.1040C>T​(p.Ser347Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000612 in 1,536,046 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S347S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (1 hom.)
• Consequence: MCIDAS NM_001190787.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.24
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2785827).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00023 (35/152296) while in subpopulation AFR AF = 0.000842 (35/41558). AF 95% confidence interval is 0.000622. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1040C>T	p.Ser347Phe	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.1040C>T	p.Ser347Phe	missense	Exon 7 of 7	ENSP00000426359.1	D6RGH6
	MCIDAS	ENST00000513468.5	TSL:5	n.*504C>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422165.1	I6L8E2
	MCIDAS	ENST00000513468.5	TSL:5	n.*504C>T		3_prime_UTR	Exon 7 of 7	ENSP00000422165.1	I6L8E2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000821

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: 0.00

GnomAD2 exomes AF: 0.000104 AC: 14 AN: 134946 AF XY: 0.0000681

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000426 AC: 59 AN: 1383750 Hom.: 1 Cov.: 30 AF XY: 0.0000439 AC XY: 30 AN XY: 682804

African (AFR) AF: 0.00127 AC: 40 AN: 31592

American (AMR) AF: 0.000140 AC: 5 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: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1078878

Other (OTH) AF: 0.0000518 AC: 3 AN: 57894

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74464

African (AFR) AF: 0.000842 AC: 35 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000370

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ciliary dyskinesia, primary, 42 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.18		Loss of disorder (P = 0.0372)
MVP		0.47
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.43
gMVP		0.79
Mutation Taster		=36/64	disease causing

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: rs561481156; hg19: chr5-54516312;