rs78575519

Variant names:

• chr4-78421957-G-A
• rs78575519
• NM_025074.7:c.4635G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-78421957-G-A
• chr4-78421957-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.4635G>A​(p.Pro1545Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,612,866 control chromosomes in the GnomAD database, including 40,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2599 hom., cov: 30)
  • Exomes 𝑓: 0.22 (38264 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.01
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-78421957-G-A is Benign according to our data. Variant chr4-78421957-G-A is described in ClinVar as Benign. ClinVar VariationId is 261807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.4635G>A	p.Pro1545Pro	synonymous_variant	Exon 34 of 74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.4635G>A	p.Pro1545Pro	synonymous_variant	Exon 34 of 42		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.4635G>A	p.Pro1545Pro	synonymous_variant	Exon 34 of 74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26307 AN: 151726 Hom.: 2599 Cov.: 30

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.0819

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.170

GnomAD2 exomes AF: 0.177 AC: 43928 AN: 248534 AF XY: 0.175

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.220 AC: 320878 AN: 1461024 Hom.: 38264 Cov.: 34 AF XY: 0.215 AC XY: 156608 AN XY: 726762

African (AFR) AF: 0.0874 AC: 2925 AN: 33470

American (AMR) AF: 0.165 AC: 7366 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3486 AN: 26116

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39682

South Asian (SAS) AF: 0.0917 AC: 7898 AN: 86164

European-Finnish (FIN) AF: 0.212 AC: 11317 AN: 53372

Middle Eastern (MID) AF: 0.113 AC: 648 AN: 5760

European-Non Finnish (NFE) AF: 0.248 AC: 275690 AN: 1111406

Other (OTH) AF: 0.191 AC: 11528 AN: 60350

GnomAD4 genome AF: 0.173 AC: 26314 AN: 151842 Hom.: 2599 Cov.: 30 AF XY: 0.169 AC XY: 12537 AN XY: 74184

African (AFR) AF: 0.0956 AC: 3961 AN: 41438

American (AMR) AF: 0.176 AC: 2680 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5146

South Asian (SAS) AF: 0.0824 AC: 394 AN: 4782

European-Finnish (FIN) AF: 0.199 AC: 2097 AN: 10530

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16146 AN: 67922

Other (OTH) AF: 0.169 AC: 355 AN: 2104

Alfa AF: 0.208 Hom.: 1850

Bravo AF: 0.167

Asia WGS AF: 0.0470 AC: 165 AN: 3478

EpiCase AF: 0.220

EpiControl AF: 0.225

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1 Benign:1

Jan 12, 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	-0.85
CADD	Benign	0.24
DANN	Benign	0.51
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs78575519; hg19: chr4-79343111;