rs11098194

Variant names:

• chr4-78479714-C-T
• rs11098194
• NM_025074.7:c.8439C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.8439C>T​(p.Asp2813Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,576,474 control chromosomes in the GnomAD database, including 106,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8800 hom., cov: 33)
  • Exomes 𝑓: 0.37 (97207 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.37
• Publications: 19 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.203).
• BP6: Variant 4-78479714-C-T is Benign according to our data. Variant chr4-78479714-C-T is described in ClinVar as Benign. ClinVar VariationId is 261815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.8439C>T	p.Asp2813Asp	synonymous_variant	Exon 56 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.8439C>T	p.Asp2813Asp	synonymous_variant	Exon 56 of 74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.8439C>T	p.Asp2813Asp	synonymous_variant	Exon 56 of 64			ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49456 AN: 151998 Hom.: 8789 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.328

GnomAD2 exomes AF: 0.371 AC: 81900 AN: 220760 AF XY: 0.366

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.482

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.315

Gnomad FIN exome AF: 0.443

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.365 AC: 520352 AN: 1424358 Hom.: 97207 Cov.: 31 AF XY: 0.363 AC XY: 255628 AN XY: 704030

African (AFR) AF: 0.171 AC: 5630 AN: 32996

American (AMR) AF: 0.470 AC: 20032 AN: 42666

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7291 AN: 23778

East Asian (EAS) AF: 0.305 AC: 11938 AN: 39164

South Asian (SAS) AF: 0.276 AC: 22057 AN: 79930

European-Finnish (FIN) AF: 0.443 AC: 23001 AN: 51974

Middle Eastern (MID) AF: 0.282 AC: 1544 AN: 5476

European-Non Finnish (NFE) AF: 0.375 AC: 408980 AN: 1089538

Other (OTH) AF: 0.338 AC: 19879 AN: 58836

GnomAD4 genome AF: 0.325 AC: 49496 AN: 152116 Hom.: 8800 Cov.: 33 AF XY: 0.328 AC XY: 24396 AN XY: 74356

African (AFR) AF: 0.178 AC: 7406 AN: 41526

American (AMR) AF: 0.411 AC: 6278 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3466

East Asian (EAS) AF: 0.302 AC: 1564 AN: 5178

South Asian (SAS) AF: 0.270 AC: 1305 AN: 4826

European-Finnish (FIN) AF: 0.437 AC: 4612 AN: 10558

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26120 AN: 67966

Other (OTH) AF: 0.331 AC: 698 AN: 2110

Alfa AF: 0.350 Hom.: 6532

Bravo AF: 0.320

Asia WGS AF: 0.294 AC: 1025 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fraser syndrome 1 Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.21
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11098194; hg19: chr4-79400868; COSMIC: COSV53590167;