rs7660664

Positions:

• chr4-78466288-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.7110C>T​(p.His2370=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,613,504 control chromosomes in the GnomAD database, including 100,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11113 hom., cov: 32)
  • Exomes 𝑓: 0.35 (89800 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0430

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 4-78466288-C-T is Benign according to our data. Variant chr4-78466288-C-T is described in ClinVar as [Benign]. Clinvar id is 261812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78466288-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.7110C>T	p.His2370=	synonymous_variant	50/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.7110C>T	p.His2370=	synonymous_variant	50/74	5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.7110C>T	p.His2370=	synonymous_variant	50/64

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56744 AN: 151962 Hom.: 11097 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.370

GnomAD3 exomes AF: 0.311 AC: 77544 AN: 249080 Hom.: 13041 AF XY: 0.306 AC XY: 41347 AN XY: 135076

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.226

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.346 AC: 505158 AN: 1461424 Hom.: 89800 Cov.: 44 AF XY: 0.340 AC XY: 247057 AN XY: 727012

Gnomad4 AFR exome AF: 0.487

Gnomad4 AMR exome AF: 0.235

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.320

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.347

GnomAD4 genome AF: 0.373 AC: 56798 AN: 152080 Hom.: 11113 Cov.: 32 AF XY: 0.366 AC XY: 27217 AN XY: 74346

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.366

Alfa AF: 0.374 Hom.: 5808

Bravo AF: 0.378

Asia WGS AF: 0.245 AC: 853 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.360

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Fraser syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.6
DANN	Benign	0.35

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: rs7660664; hg19: chr4-79387442; COSMIC: COSV53606655;