Genetic Variant MUC5AC:p.Arg1820Gln (chr11-1183604-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001304359.2(MUC5AC):c.5459G>A(p.Arg1820Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 629,976 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.13 ( 0 hom., cov: 28)

Exomes 𝑓: 0.13 ( 7 hom. )

Consequence

MUC5AC
NM_001304359.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.361

Variant links:

Genes affected

MUC5AC (HGNC:7515): (mucin 5AC, oligomeric mucus/gel-forming) Predicted to be an extracellular matrix structural constituent. Involved in phosphatidylinositol-mediated signaling. Located in cytoplasm; extracellular space; and mucus layer. Implicated in dry eye syndrome. Biomarker of several diseases, including Sjogren's syndrome; biliary tract disease (multiple); cystic fibrosis; eye disease (multiple); and pancreatic cancer (multiple). [provided by Alliance of Genome Resources, Apr 2022]

MUC5AC links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016388893).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC5AC	NM_001304359.2 link	c.5459G>A	p.Arg1820Gln	missense_variant	Exon 31 of 49	ENST00000621226.2	NP_001291288.1	P98088

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC5AC	ENST00000621226.2 link	c.5459G>A	p.Arg1820Gln	missense_variant	Exon 31 of 49	5	NM_001304359.2	ENSP00000485659.1		P98088

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

19786

AN:

147360

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.194

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.0627

Gnomad EAS

AF:

0.00389

Gnomad SAS

AF:

0.0523

Gnomad FIN

AF:

0.213

Gnomad MID

AF:

0.0833

Gnomad NFE

AF:

0.162

Gnomad OTH

AF:

0.120

GnomAD4 exome

AF:

0.134

AC:

64423

AN:

482510

Hom.:

Cov.:

AF XY:

0.130

AC XY:

33429

AN XY:

256914

show subpopulations

Gnomad4 AFR exome

AF:

0.113

AC:

1463

AN:

12968

Gnomad4 AMR exome

AF:

0.0823

AC:

2196

AN:

26694

Gnomad4 ASJ exome

AF:

0.0656

AC:

923

AN:

14078

Gnomad4 EAS exome

AF:

0.00362

AC:

122

AN:

33730

Gnomad4 SAS exome

AF:

0.0564

AC:

2696

AN:

47834

Gnomad4 FIN exome

AF:

0.198

AC:

6463

AN:

32572

Gnomad4 NFE exome

AF:

0.164

AC:

46560

AN:

283942

Gnomad4 Remaining exome

AF:

0.136

AC:

3698

AN:

27156

Heterozygous variant carriers

4506

9012

13518

18024

22530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.134

AC:

19782

AN:

147466

Hom.:

Cov.:

AF XY:

0.134

AC XY:

9616

AN XY:

71944

show subpopulations

Gnomad4 AFR

AF:

0.109

AC:

0.109096

AN:

0.109096

Gnomad4 AMR

AF:

0.109

AC:

0.108952

AN:

0.108952

Gnomad4 ASJ

AF:

0.0627

AC:

0.0627178

AN:

0.0627178

Gnomad4 EAS

AF:

0.00390

AC:

0.00389864

AN:

0.00389864

Gnomad4 SAS

AF:

0.0526

AC:

0.0525641

AN:

0.0525641

Gnomad4 FIN

AF:

0.213

AC:

0.213084

AN:

0.213084

Gnomad4 NFE

AF:

0.162

AC:

0.161752

AN:

0.161752

Gnomad4 OTH

AF:

0.119

AC:

0.119048

AN:

0.119048

Heterozygous variant carriers

1017

2034

3050

4067

5084

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

228

456

684

912

1140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.145

Hom.:

ESP6500AA

AF:

0.0811

AC:

142

ESP6500EA

AF:

0.132

AC:

526

ExAC

AF:

0.126

AC:

14988

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Keratoconus

Uncertain:1

Apr 01, 2023

Institute of Human Genetics, Polish Academy of Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

DEOGEN2

Benign

0.082

FATHMM_MKL

Benign

0.050

MetaRNN

Benign

0.0016

Sift4G

Benign

0.092

Vest4

0.11

GERP RS

0.74

gMVP

0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over