4-78057987-C-T

Variant names:

• chr4-78057987-C-T
• rs34237418
• NM_025074.7:c.-23C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.707
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Fraser syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Fraser syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.-23C>T		5_prime_UTR_variant	Exon 1 of 74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.-23C>T		5_prime_UTR_variant	Exon 1 of 42		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.-23C>T		5_prime_UTR_variant	Exon 1 of 74	5	NM_025074.7	ENSP00000422834.2

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

GnomAD2 exomes AF: 0.164 AC: 40598 AN: 248250 AF XY: 0.162

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 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

African (AFR) AF: 0.0532 AC: 1780 AN: 33440

American (AMR) AF: 0.185 AC: 8264 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3940 AN: 26098

East Asian (EAS) AF: 0.0194 AC: 770 AN: 39686

South Asian (SAS) AF: 0.101 AC: 8707 AN: 86176

European-Finnish (FIN) AF: 0.203 AC: 10808 AN: 53274

Middle Eastern (MID) AF: 0.156 AC: 896 AN: 5762

European-Non Finnish (NFE) AF: 0.209 AC: 231599 AN: 1110142

Other (OTH) AF: 0.176 AC: 10643 AN: 60302

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

African (AFR) AF: 0.0577 AC: 2398 AN: 41564

American (AMR) AF: 0.195 AC: 2982 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 527 AN: 3470

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5176

South Asian (SAS) AF: 0.104 AC: 502 AN: 4826

European-Finnish (FIN) AF: 0.210 AC: 2226 AN: 10594

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13977 AN: 67992

Other (OTH) AF: 0.154 AC: 325 AN: 2110

Alfa AF: 0.193 Hom.: 4074

Bravo AF: 0.149

Asia WGS AF: 0.0770 AC: 270 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fraser syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.71
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=287/13	polymorphism (auto)

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

Other links and lift over

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