NM_025074.7:c.9116-11T>C

Variant names:

• chr4-78499710-T-C
• rs7677541
• NM_025074.7:c.9116-11T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):​c.9116-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,608,900 control chromosomes in the GnomAD database, including 183,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21242 hom., cov: 33)
  • Exomes 𝑓: 0.46 (162683 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Scores: Splicing: ADA: 0.005685
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.303
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-78499710-T-C is Benign according to our data. Variant chr4-78499710-T-C is described in ClinVar as Benign. ClinVar VariationId is 261817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.9116-11T>C		intron_variant	Intron 60 of 73	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.9116-11T>C		intron_variant	Intron 60 of 73	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.9116-11T>C		intron_variant	Intron 60 of 63			ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78680 AN: 151750 Hom.: 21225 Cov.: 33

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.533

GnomAD2 exomes AF: 0.505 AC: 125142 AN: 248046 AF XY: 0.512

Gnomad AFR exome AF: 0.649

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.714

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.431

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.464 AC: 676052 AN: 1457034 Hom.: 162683 Cov.: 31 AF XY: 0.470 AC XY: 340521 AN XY: 724824

African (AFR) AF: 0.658 AC: 21953 AN: 33372

American (AMR) AF: 0.450 AC: 20100 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 15538 AN: 26064

East Asian (EAS) AF: 0.714 AC: 28339 AN: 39664

South Asian (SAS) AF: 0.660 AC: 56738 AN: 85964

European-Finnish (FIN) AF: 0.439 AC: 23419 AN: 53350

Middle Eastern (MID) AF: 0.619 AC: 3372 AN: 5450

European-Non Finnish (NFE) AF: 0.430 AC: 476095 AN: 1108366

Other (OTH) AF: 0.507 AC: 30498 AN: 60160

GnomAD4 genome AF: 0.519 AC: 78745 AN: 151866 Hom.: 21242 Cov.: 33 AF XY: 0.522 AC XY: 38747 AN XY: 74220

African (AFR) AF: 0.647 AC: 26760 AN: 41392

American (AMR) AF: 0.474 AC: 7232 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2041 AN: 3466

East Asian (EAS) AF: 0.716 AC: 3689 AN: 5152

South Asian (SAS) AF: 0.662 AC: 3194 AN: 4822

European-Finnish (FIN) AF: 0.449 AC: 4727 AN: 10518

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.432 AC: 29383 AN: 67946

Other (OTH) AF: 0.532 AC: 1121 AN: 2106

Alfa AF: 0.527 Hom.: 9994

Bravo AF: 0.524

Asia WGS AF: 0.670 AC: 2330 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 25, 2019

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

- -

Fraser syndrome 1 Benign:3

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.4
DANN	Benign	0.39
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0057
dbscSNV1_RF	Benign	0.036
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: rs7677541; hg19: chr4-79420864;