4-78057825-G-T

Variant names:

• chr4-78057825-G-T
• rs559206528
• NM_025074.7:c.-185G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_025074.7(FRAS1):​c.-185G>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 0.0000906 in 584,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: FRAS1 NM_025074.7 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.616
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000109 (47/432642) while in subpopulation SAS AF = 0.000829 (33/39804). AF 95% confidence interval is 0.000607. There are 0 homozygotes in GnomAdExome4. There are 33 alleles in the male GnomAdExome4 subpopulation. Median coverage is 5. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.-185G>T		5_prime_UTR_variant	Exon 1 of 74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.-185G>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.-185G>T		5_prime_UTR_variant	Exon 1 of 74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 47 AN: 432642 Hom.: 0 Cov.: 5 AF XY: 0.000146 AC XY: 33 AN XY: 226448

African (AFR) AF: 0.00 AC: 0 AN: 11980

American (AMR) AF: 0.00 AC: 0 AN: 18054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13150

East Asian (EAS) AF: 0.00 AC: 0 AN: 30238

South Asian (SAS) AF: 0.000829 AC: 33 AN: 39804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1892

European-Non Finnish (NFE) AF: 0.0000381 AC: 10 AN: 262652

Other (OTH) AF: 0.000158 AC: 4 AN: 25276

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fraser syndrome 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.7
DANN	Benign	0.69
PhyloP100		-0.62
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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: rs559206528; hg19: chr4-78978979;