4-78534579-C-T

Position:

• chr4-78534579-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.11056C>T​(p.Leu3686Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,607,578 control chromosomes in the GnomAD database, including 173,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15019 hom., cov: 33)
  • Exomes 𝑓: 0.46 (158535 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.15

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=-0.62).
• BP6: Variant 4-78534579-C-T is Benign according to our data. Variant chr4-78534579-C-T is described in ClinVar as [Benign]. Clinvar id is 261802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78534579-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.11056C>T	p.Leu3686Leu	synonymous_variant	71/74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.11056C>T	p.Leu3686Leu	synonymous_variant	71/74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65967 AN: 151988 Hom.: 15023 Cov.: 33

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.466

GnomAD3 exomes AF: 0.490 AC: 121714 AN: 248288 Hom.: 31742 AF XY: 0.500 AC XY: 67334 AN XY: 134714

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.468

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.791

Gnomad SAS exome AF: 0.648

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.458 AC: 666087 AN: 1455472 Hom.: 158535 Cov.: 34 AF XY: 0.464 AC XY: 336008 AN XY: 724348

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.469

Gnomad4 ASJ exome AF: 0.583

Gnomad4 EAS exome AF: 0.782

Gnomad4 SAS exome AF: 0.645

Gnomad4 FIN exome AF: 0.435

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.487

GnomAD4 genome AF: 0.434 AC: 65987 AN: 152106 Hom.: 15019 Cov.: 33 AF XY: 0.441 AC XY: 32756 AN XY: 74360

Gnomad4 AFR AF: 0.345

Gnomad4 AMR AF: 0.465

Gnomad4 ASJ AF: 0.574

Gnomad4 EAS AF: 0.794

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.443

Gnomad4 NFE AF: 0.429

Gnomad4 OTH AF: 0.466

Alfa AF: 0.445 Hom.: 35722

Bravo AF: 0.431

Asia WGS AF: 0.675 AC: 2345 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.454

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fraser syndrome 1 Benign:3

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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.4
DANN	Benign	0.64

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: rs4975139; hg19: chr4-79455733; COSMIC: COSV53610394;