rs931605

chr4-78522683-A-T

Variant summary

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

The NM_025074.7(FRAS1):c.10683A>T(p.Glu3561Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,605,288 control chromosomes in the GnomAD database, including 29,222 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1781 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27441 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.401

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023269355).
• BP6: Variant 4-78522683-A-T is Benign according to our data. Variant chr4-78522683-A-T is described in ClinVar as [Benign]. Clinvar id is 261797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78522683-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.10683A>T	p.Glu3561Asp	missense_variant	69/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.10683A>T	p.Glu3561Asp	missense_variant	69/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21222 AN: 152052 Hom.: 1781 Cov.: 32

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.135 AC: 32513 AN: 240784 Hom.: 2837 AF XY: 0.135 AC XY: 17596 AN XY: 130378

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00171

Gnomad SAS exome AF: 0.0575

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.184 AC: 266904 AN: 1453118 Hom.: 27441 Cov.: 32 AF XY: 0.180 AC XY: 129775 AN XY: 722410

Gnomad4 AFR exome AF: 0.0740

Gnomad4 AMR exome AF: 0.0814

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.0582

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.212

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.139 AC: 21222 AN: 152170 Hom.: 1781 Cov.: 32 AF XY: 0.134 AC XY: 10006 AN XY: 74406

Gnomad4 AFR AF: 0.0776

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0531

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.133

Alfa AF: 0.182 Hom.: 2131

Bravo AF: 0.135

TwinsUK AF: 0.229 AC: 848

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.0776 AC: 290

ESP6500EA AF: 0.197 AC: 1622

ExAC AF: 0.136 AC: 16448

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fraser syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.053
Dann	Benign	0.050
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.41	T
Sift4G	Benign	1.0	T
Vest4		0.029
ClinPred		0.0010	T
GERP RS		-1.1
gMVP		0.15

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: rs931605; hg19: chr4-79443837;