5-38407128-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152403.4(EGFLAM):c.1129G>A(p.Gly377Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

EGFLAM
NM_152403.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.12

Variant links:

Genes affected

EGFLAM (HGNC:26810): (EGF like, fibronectin type III and laminin G domains) Predicted to enable calcium ion binding activity and glycosaminoglycan binding activity. Predicted to be involved in animal organ morphogenesis and tissue development. Predicted to act upstream of or within extracellular matrix organization; peptide cross-linking via chondroitin 4-sulfate glycosaminoglycan; and positive regulation of cell-substrate adhesion. Part of cell surface. [provided by Alliance of Genome Resources, Apr 2022]

EGFLAM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EGFLAM	NM_152403.4 linkuse as main transcript	c.1129G>A	p.Gly377Ser	missense_variant	8/22	ENST00000322350.10
EGFLAM	NM_001205301.2 linkuse as main transcript	c.1129G>A	p.Gly377Ser	missense_variant	8/23
EGFLAM	NM_182798.3 linkuse as main transcript	c.427G>A	p.Gly143Ser	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFLAM	ENST00000322350.10 linkuse as main transcript	c.1129G>A	p.Gly377Ser	missense_variant	8/22	1	NM_152403.4	P3	Q63HQ2-2
EGFLAM	ENST00000354891.7 linkuse as main transcript	c.1129G>A	p.Gly377Ser	missense_variant	8/23	1		A2	Q63HQ2-1
EGFLAM	ENST00000397202.6 linkuse as main transcript	c.-364+3237G>A		intron_variant		1			Q63HQ2-3
EGFLAM	ENST00000336740.10 linkuse as main transcript	c.427G>A	p.Gly143Ser	missense_variant	3/17	2			Q63HQ2-4

Frequencies

GnomAD3 genomes

AF:

0.000152

AC:

AN:

151598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000166

AC:

AN:

247398

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

134074

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00150

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000236

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00126

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000152

AC:

AN:

151598

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74054

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000379

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.1129G>A (p.G377S) alteration is located in exon 8 (coding exon 8) of the EGFLAM gene. This alteration results from a G to A substitution at nucleotide position 1129, causing the glycine (G) at amino acid position 377 to be replaced by a serine (S). 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

0.13

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.91

MVP

0.92

MPC

0.49

ClinPred

0.56

GERP RS

5.7

Varity_R

0.85

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: 18

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