4-78464478-C-T

Variant names:

• chr4-78464478-C-T
• rs13123710
• NM_025074.7:c.6924C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.6924C>T​(p.Val2308Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0736 in 1,613,782 control chromosomes in the GnomAD database, including 5,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (325 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4705 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.79
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-78464478-C-T is Benign according to our data. Variant chr4-78464478-C-T is described in ClinVar as Benign. ClinVar VariationId is 261810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.6924C>T	p.Val2308Val	synonymous_variant	Exon 49 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.6924C>T	p.Val2308Val	synonymous_variant	Exon 49 of 74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.6924C>T	p.Val2308Val	synonymous_variant	Exon 49 of 64			ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8393 AN: 152126 Hom.: 326 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0575 AC: 14312 AN: 248878 AF XY: 0.0582

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0541

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.0940

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0755 AC: 110315 AN: 1461538 Hom.: 4705 Cov.: 32 AF XY: 0.0742 AC XY: 53939 AN XY: 727068

African (AFR) AF: 0.0104 AC: 349 AN: 33478

American (AMR) AF: 0.0244 AC: 1093 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0558 AC: 1457 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39698

South Asian (SAS) AF: 0.0297 AC: 2558 AN: 86248

European-Finnish (FIN) AF: 0.0937 AC: 5003 AN: 53396

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5766

European-Non Finnish (NFE) AF: 0.0862 AC: 95867 AN: 1111724

Other (OTH) AF: 0.0636 AC: 3840 AN: 60372

GnomAD4 genome AF: 0.0551 AC: 8391 AN: 152244 Hom.: 325 Cov.: 32 AF XY: 0.0539 AC XY: 4009 AN XY: 74432

African (AFR) AF: 0.0150 AC: 625 AN: 41534

American (AMR) AF: 0.0418 AC: 640 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4826

European-Finnish (FIN) AF: 0.0888 AC: 941 AN: 10594

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0837 AC: 5694 AN: 68006

Other (OTH) AF: 0.0407 AC: 86 AN: 2114

Alfa AF: 0.0687 Hom.: 683

Bravo AF: 0.0494

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0739

EpiControl AF: 0.0756

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

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	-0.32
CADD	Benign	8.5
DANN	Benign	0.65
PhyloP100		2.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs13123710; hg19: chr4-79385632; COSMIC: COSV53626018;