chr4-78482528-C-T

Variant names:

• chr4-78482528-C-T
• rs41327848
• NM_025074.7:c.8745C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.8745C>T​(p.Phe2915Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,612,948 control chromosomes in the GnomAD database, including 37,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4207 hom., cov: 33)
  • Exomes 𝑓: 0.20 (33217 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 4-78482528-C-T is Benign according to our data. Variant chr4-78482528-C-T is described in ClinVar as [Benign]. Clinvar id is 261816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78482528-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.8745C>T	p.Phe2915Phe	synonymous_variant	Exon 58 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.8745C>T	p.Phe2915Phe	synonymous_variant	Exon 58 of 74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.8745C>T	p.Phe2915Phe	synonymous_variant	Exon 58 of 64			ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33423 AN: 152012 Hom.: 4204 Cov.: 33

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.163 AC: 40480 AN: 248552 Hom.: 4274 AF XY: 0.159 AC XY: 21422 AN XY: 134798

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.0937

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.0627

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.203 AC: 296670 AN: 1460818 Hom.: 33217 Cov.: 34 AF XY: 0.198 AC XY: 143856 AN XY: 726656

Gnomad4 AFR exome AF: 0.326

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.00239

Gnomad4 SAS exome AF: 0.0643

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.220 AC: 33457 AN: 152130 Hom.: 4207 Cov.: 33 AF XY: 0.212 AC XY: 15761 AN XY: 74388

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.0568

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.196

Alfa AF: 0.200 Hom.: 1846

Bravo AF: 0.223

Asia WGS AF: 0.0560 AC: 197 AN: 3478

EpiCase AF: 0.200

EpiControl AF: 0.206

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41327848; hg19: chr4-79403682; COSMIC: COSV53608178;