4-78317495-T-C

Position:

• chr4-78317495-T-C

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.1947T>C​(p.His649His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,612,350 control chromosomes in the GnomAD database, including 467,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46225 hom., cov: 32)
  • Exomes 𝑓: 0.76 (421402 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.44

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]

FRAS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 4-78317495-T-C is Benign according to our data. Variant chr4-78317495-T-C is described in ClinVar as [Benign]. Clinvar id is 194790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78317495-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.1947T>C	p.His649His	synonymous_variant	17/74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.1947T>C	p.His649His	synonymous_variant	17/42		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.1947T>C	p.His649His	synonymous_variant	17/74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118084 AN: 152034 Hom.: 46182 Cov.: 32

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.739 AC: 183163 AN: 247960 Hom.: 68388 AF XY: 0.729 AC XY: 98154 AN XY: 134568

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.688

Gnomad SAS exome AF: 0.590

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.758 AC: 1106463 AN: 1460198 Hom.: 421402 Cov.: 43 AF XY: 0.752 AC XY: 546575 AN XY: 726390

Gnomad4 AFR exome AF: 0.846

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.678

Gnomad4 EAS exome AF: 0.712

Gnomad4 SAS exome AF: 0.597

Gnomad4 FIN exome AF: 0.808

Gnomad4 NFE exome AF: 0.772

Gnomad4 OTH exome AF: 0.741

GnomAD4 genome AF: 0.777 AC: 118192 AN: 152152 Hom.: 46225 Cov.: 32 AF XY: 0.772 AC XY: 57385 AN XY: 74362

Gnomad4 AFR AF: 0.848

Gnomad4 AMR AF: 0.724

Gnomad4 ASJ AF: 0.671

Gnomad4 EAS AF: 0.685

Gnomad4 SAS AF: 0.595

Gnomad4 FIN AF: 0.797

Gnomad4 NFE AF: 0.768

Gnomad4 OTH AF: 0.742

Alfa AF: 0.756 Hom.: 91900

Bravo AF: 0.777

Asia WGS AF: 0.635 AC: 2208 AN: 3478

EpiCase AF: 0.748

EpiControl AF: 0.750

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2019	- -

Fraser syndrome 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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_noAF	Benign	-0.93
CADD	Benign	0.0070
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs345514; hg19: chr4-79238649; COSMIC: COSV53630314;