4-78516001-C-T

Variant names:

• chr4-78516001-C-T
• rs3749487
• NM_025074.7:c.10377C>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.10377C>T​(p.Thr3459Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,611,934 control chromosomes in the GnomAD database, including 25,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T3459T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2692 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23232 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.67
• Publications: 13 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=0.208).
• BP6: Variant 4-78516001-C-T is Benign according to our data. Variant chr4-78516001-C-T is described in ClinVar as Benign. ClinVar VariationId is 261795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.10377C>T	p.Thr3459Thr	synonymous_variant	Exon 66 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10377C>T	p.Thr3459Thr	synonymous_variant	Exon 66 of 74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28199 AN: 152072 Hom.: 2690 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.180 AC: 44314 AN: 246138 AF XY: 0.179

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.173

GnomAD4 exome AF: 0.177 AC: 258534 AN: 1459744 Hom.: 23232 Cov.: 33 AF XY: 0.176 AC XY: 127810 AN XY: 725986

African (AFR) AF: 0.192 AC: 6422 AN: 33442

American (AMR) AF: 0.143 AC: 6395 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 6821 AN: 26108

East Asian (EAS) AF: 0.212 AC: 8375 AN: 39590

South Asian (SAS) AF: 0.144 AC: 12392 AN: 85996

European-Finnish (FIN) AF: 0.205 AC: 10964 AN: 53356

Middle Eastern (MID) AF: 0.222 AC: 1279 AN: 5762

European-Non Finnish (NFE) AF: 0.175 AC: 194391 AN: 1110602

Other (OTH) AF: 0.191 AC: 11495 AN: 60320

GnomAD4 genome AF: 0.185 AC: 28208 AN: 152190 Hom.: 2692 Cov.: 32 AF XY: 0.186 AC XY: 13859 AN XY: 74408

African (AFR) AF: 0.186 AC: 7738 AN: 41514

American (AMR) AF: 0.169 AC: 2590 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 933 AN: 3472

East Asian (EAS) AF: 0.232 AC: 1198 AN: 5164

South Asian (SAS) AF: 0.140 AC: 677 AN: 4826

European-Finnish (FIN) AF: 0.201 AC: 2129 AN: 10594

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.182 AC: 12349 AN: 68004

Other (OTH) AF: 0.187 AC: 395 AN: 2112

Alfa AF: 0.176 Hom.: 2162

Bravo AF: 0.183

Asia WGS AF: 0.207 AC: 721 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

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	-0.51
CADD	Benign	0.28
DANN	Benign	0.45
PhyloP100		-1.7
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: rs3749487; hg19: chr4-79437155; COSMIC: COSV53606678;