5-38370435-T-C

Position:

• chr5-38370435-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152403.4(EGFLAM):​c.685T>C​(p.Trp229Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,613,854 control chromosomes in the GnomAD database, including 36,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (5451 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30557 hom.)
• Consequence: EGFLAM NM_152403.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.303

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.732277E-4).
• BP6: Variant 5-38370435-T-C is Benign according to our data. Variant chr5-38370435-T-C is described in ClinVar as [Benign]. Clinvar id is 1235521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFLAM	NM_152403.4	c.685T>C	p.Trp229Arg	missense_variant	6/22	ENST00000322350.10	NP_689616.2
EGFLAM	NM_001205301.2	c.685T>C	p.Trp229Arg	missense_variant	6/23		NP_001192230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFLAM	ENST00000322350.10	c.685T>C	p.Trp229Arg	missense_variant	6/22	1	NM_152403.4	ENSP00000313084	P3
EGFLAM	ENST00000354891.7	c.685T>C	p.Trp229Arg	missense_variant	6/23	1		ENSP00000346964	A2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 38039 AN: 152050 Hom.: 5434 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.203 AC: 50838 AN: 250688 Hom.: 5557 AF XY: 0.201 AC XY: 27305 AN XY: 135512

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.212

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.200 AC: 292735 AN: 1461684 Hom.: 30557 Cov.: 33 AF XY: 0.200 AC XY: 145700 AN XY: 727126

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.210

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.250 AC: 38096 AN: 152170 Hom.: 5451 Cov.: 32 AF XY: 0.249 AC XY: 18534 AN XY: 74378

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.199

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.233

Alfa AF: 0.198 Hom.: 6221

Bravo AF: 0.257

TwinsUK AF: 0.197 AC: 730

ALSPAC AF: 0.193 AC: 744

ESP6500AA AF: 0.396 AC: 1746

ESP6500EA AF: 0.193 AC: 1663

ExAC AF: 0.210 AC: 25538

Asia WGS AF: 0.201 AC: 696 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.195

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2019	This variant is associated with the following publications: (PMID: 28339009) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.5
DANN	Benign	0.68
DEOGEN2	Benign	0.042	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.29	T;T
MetaRNN	Benign	0.00027	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.93	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.028
Sift	Benign	0.66	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.0	B;B
Vest4		0.028
MutPred		0.35		Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);
MPC		0.16
ClinPred		0.000015	T
GERP RS		-2.0
Varity_R		0.082
gMVP		0.21

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

Other links and lift over

dbSNP: rs1465567; hg19: chr5-38370537; COSMIC: COSV59295733;