Genetic Variant NM_007046.4:c.407C>T (chr2-27080848-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_007046.4(EMILIN1):c.407C>T(p.Ala136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,612,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

EMILIN1
NM_007046.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.759

Variant links:

Genes affected

EMILIN1 (HGNC:19880): (elastin microfibril interfacer 1) This gene encodes an extracellular matrix glycoprotein that is characterized by an N-terminal microfibril interface domain, a coiled-coiled alpha-helical domain, a collagenous domain and a C-terminal globular C1q domain. The encoded protein associates with elastic fibers at the interface between elastin and microfibrils and may play a role in the development of elastic tissues including large blood vessels, dermis, heart and lung. [provided by RefSeq, Sep 2009]

EMILIN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07432228).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000591 (9/152236) while in subpopulation AFR AF= 0.000193 (8/41452). AF 95% confidence interval is 0.0000956. There are 0 homozygotes in gnomad4. There are 5 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

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMILIN1	NM_007046.4 link	c.407C>T	p.Ala136Val	missense_variant	Exon 3 of 8	ENST00000380320.9	NP_008977.1	Q9Y6C2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMILIN1	ENST00000380320.9 link	c.407C>T	p.Ala136Val	missense_variant	Exon 3 of 8	1	NM_007046.4	ENSP00000369677.4		Q9Y6C2-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245816

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133622

show subpopulations

Gnomad AFR exome

AF:

0.0000642

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1459886

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726130

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000193

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.407C>T (p.A136V) alteration is located in exon 3 (coding exon 3) of the EMILIN1 gene. This alteration results from a C to T substitution at nucleotide position 407, causing the alanine (A) at amino acid position 136 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.68

M_CAP

Benign

0.023

MetaRNN

Benign

0.074

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.88

REVEL

Benign

0.033

Sift

Benign

0.23

Sift4G

Benign

0.45

Polyphen

0.0070

Vest4

0.099

MutPred

0.22

Gain of catalytic residue at A136 (P = 0.019);

MVP

0.69

MPC

0.18

ClinPred

0.038

GERP RS

2.1

Varity_R

0.020

gMVP

0.27

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

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