rs191105001

chr4-78507460-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_025074.7(FRAS1):c.9356A>G(p.Asn3119Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,612,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.09

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01331991).
• BP6: Variant 4-78507460-A-G is Benign according to our data. Variant chr4-78507460-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435258.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000236 (36/152300) while in subpopulation EAS AF= 0.00424 (22/5186). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.9356A>G	p.Asn3119Ser	missense_variant	62/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.9356A>G	p.Asn3119Ser	missense_variant	62/74	5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.9356A>G	p.Asn3119Ser	missense_variant	62/64

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000327 AC: 81 AN: 247618 Hom.: 0 AF XY: 0.000275 AC XY: 37 AN XY: 134396

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00410

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000103 AC: 150 AN: 1460292 Hom.: 1 Cov.: 31 AF XY: 0.0000950 AC XY: 69 AN XY: 726380

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00283

Gnomad4 SAS exome AF: 0.0000583

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74478

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000246

ESP6500AA AF: 0.000504 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000372 AC: 45

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 20, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

FRAS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2023

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	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
Sift4G	Pathogenic	0.0	D
Vest4		0.62
MVP		0.70
ClinPred		0.10	T
GERP RS		5.3
gMVP		0.39

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: rs191105001; hg19: chr4-79428614;