chr4-78539301-A-G

Position:

• chr4-78539301-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_025074.7(FRAS1):​c.11306A>G​(p.Asn3769Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,604,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 4.45

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012599647).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000902 (131/1451940) while in subpopulation AFR AF= 0.00275 (90/32754). AF 95% confidence interval is 0.00229. There are 0 homozygotes in gnomad4_exome. There are 61 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.11306A>G	p.Asn3769Ser	missense_variant	73/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.11306A>G	p.Asn3769Ser	missense_variant	73/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000134 AC: 32 AN: 238576 Hom.: 0 AF XY: 0.0000696 AC XY: 9 AN XY: 129338

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0000960

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: 0.00000908

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.0000902 AC: 131 AN: 1451940 Hom.: 0 Cov.: 32 AF XY: 0.0000845 AC XY: 61 AN XY: 721918

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0000717

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152260 Hom.: 0 Cov.: 31 AF XY: 0.000510 AC XY: 38 AN XY: 74458

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000627

ESP6500AA AF: 0.00131 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000174 AC: 21

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 3769 of the FRAS1 protein (p.Asn3769Ser). This variant is present in population databases (rs112039037, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with FRAS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 283916). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Fraser syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense c.11306A>G (p.Asn3769Ser) variant in FRAS1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn3769Ser variant is reported with an allele frequency of 0.01% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). The amino acid change p.Asn3769Ser in FRAS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 3769 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

FRAS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.75
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.78	D
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.92	T
Vest4		0.11
MVP		0.38
ClinPred		0.0098	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112039037; hg19: chr4-79460455;