Genetic Variant HMCN1:p.Gln4437Leu (chr1-186132407-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_031935.3(HMCN1):c.13310A>T(p.Gln4437Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4437R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HMCN1
NM_031935.3 missense

Scores

Splicing: ADA: 0.9955

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.50

Publications

34 publications found

Variant links:

Genes affected

HMCN1 (HGNC:19194): (hemicentin 1) This gene encodes a large extracellular member of the immunoglobulin superfamily. A similar protein in C. elegans forms long, fine tracks at specific extracellular sites that are involved in many processes such as stabilization of the germline syncytium, anchorage of mechanosensory neurons to the epidermis, and organization of hemidesmosomes in the epidermis. Mutations in this gene may be associated with age-related macular degeneration. [provided by RefSeq, Jul 2008]

HMCN1 Gene-Disease associations (from GenCC):

age related macular degeneration 1
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

HMCN1 links:

ENSG00000294274 (HGNC:):

ENSG00000294274 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HMCN1	NM_031935.3 link	c.13310A>T	p.Gln4437Leu	missense_variant	Exon 86 of 107	ENST00000271588.9	NP_114141.2
HMCN1	XM_011510038.4 link	c.13310A>T	p.Gln4437Leu	missense_variant	Exon 86 of 106		XP_011508340.1
HMCN1	XM_017002437.2 link	c.11333A>T	p.Gln3778Leu	missense_variant, splice_region_variant	Exon 75 of 96		XP_016857926.1
HMCN1	XM_047431608.1 link	c.9134A>T	p.Gln3045Leu	missense_variant, splice_region_variant	Exon 63 of 84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9 link	c.13310A>T	p.Gln4437Leu	missense_variant	Exon 86 of 107	1	NM_031935.3	ENSP00000271588.4
ENSG00000294274	ENST00000722342.1 link	n.588+3887T>A		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1454970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723754

African (AFR)

AF:

0.00

AC:

AN:

33304

American (AMR)

AF:

0.00

AC:

AN:

44178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.00

AC:

AN:

85618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107496

Other (OTH)

AF:

0.00

AC:

AN:

60042

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.35

PhyloP100

8.5

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0010

Polyphen

0.97

Vest4

0.67

MutPred

0.40

Loss of disorder (P = 0.0997);

MVP

0.58

MPC

0.41

ClinPred

0.99

GERP RS

5.4

Varity_R

0.65

gMVP

0.51

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over