4-78057945-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_025074.7(FRAS1):c.-65T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,524,990 control chromosomes in the GnomAD database, including 3,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.088 (1609 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2085 hom.)
• Consequence: FRAS1 NM_025074.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.257

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-78057945-T-C is Benign according to our data. Variant chr4-78057945-T-C is described in ClinVar as [Benign]. Clinvar id is 349648.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.-65T>C		5_prime_UTR_variant	1/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.-65T>C		5_prime_UTR_variant	1/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.-65T>C		5_prime_UTR_variant	1/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.0873 AC: 13283 AN: 152082 Hom.: 1598 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.0641

GnomAD4 exome AF: 0.0187 AC: 25711 AN: 1372790 Hom.: 2085 Cov.: 20 AF XY: 0.0199 AC XY: 13668 AN XY: 685732

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.132

Gnomad4 SAS exome AF: 0.0849

Gnomad4 FIN exome AF: 0.000495

Gnomad4 NFE exome AF: 0.000855

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0877 AC: 13343 AN: 152200 Hom.: 1609 Cov.: 32 AF XY: 0.0878 AC XY: 6533 AN XY: 74440

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.0505

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0347 Hom.: 224

Bravo AF: 0.0967

Asia WGS AF: 0.126 AC: 437 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fraser syndrome 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6832285; hg19: chr4-78979099;