Variant 1-186132407-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000271588.9(HMCN1):c.13310A>T(p.Gln4437Leu) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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
ENST00000271588.9 missense, splice_region

Scores

Splicing: ADA: 0.9955

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.50

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HMCN1	NM_031935.3 linkuse as main transcript	c.13310A>T	p.Gln4437Leu	missense_variant, splice_region_variant	86/107	ENST00000271588.9	NP_114141.2
HMCN1	XM_011510038.4 linkuse as main transcript	c.13310A>T	p.Gln4437Leu	missense_variant, splice_region_variant	86/106		XP_011508340.1
HMCN1	XM_017002437.2 linkuse as main transcript	c.11333A>T	p.Gln3778Leu	missense_variant, splice_region_variant	75/96		XP_016857926.1
HMCN1	XM_047431608.1 linkuse as main transcript	c.9134A>T	p.Gln3045Leu	missense_variant, splice_region_variant	63/84		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9 linkuse as main transcript	c.13310A>T	p.Gln4437Leu	missense_variant, splice_region_variant	86/107	1	NM_031935.3	ENSP00000271588	P1	Q96RW7-1

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

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

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

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

MutationTaster

Benign

2.3e-9

P;P

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

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over