4-78057987-C-T

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.-23C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,611,780 control chromosomes in the GnomAD database, including 30,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2236 hom., cov: 32)
  • Exomes 𝑓: 0.19 (28203 hom.)
• Consequence: FRAS1 NM_025074.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.707

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=-0.53).
• BP6: Variant 4-78057987-C-T is Benign according to our data. Variant chr4-78057987-C-T is described in ClinVar as [Benign]. Clinvar id is 349649.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-78057987-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.-23C>T		5_prime_UTR_variant	1/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.-23C>T		5_prime_UTR_variant	1/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.-23C>T		5_prime_UTR_variant	1/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23376 AN: 152124 Hom.: 2236 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0183

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.164 AC: 40598 AN: 248250 Hom.: 3902 AF XY: 0.162 AC XY: 21828 AN XY: 134650

Gnomad AFR exome AF: 0.0518

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0188

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.190 AC: 277407 AN: 1459538 Hom.: 28203 Cov.: 31 AF XY: 0.187 AC XY: 135962 AN XY: 726100

Gnomad4 AFR exome AF: 0.0532

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0194

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.154 AC: 23376 AN: 152242 Hom.: 2236 Cov.: 32 AF XY: 0.151 AC XY: 11230 AN XY: 74440

Gnomad4 AFR AF: 0.0577

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.154

Alfa AF: 0.181 Hom.: 793

Bravo AF: 0.149

Asia WGS AF: 0.0770 AC: 270 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 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	-0.53
Cadd	Benign	8.4
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs34237418; hg19: chr4-78979141; COSMIC: COSV53603985;