chr4-78470102-T-C

Variant names:

• chr4-78470102-T-C
• rs7664505
• NM_025074.7:c.7371+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.7371+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,580,422 control chromosomes in the GnomAD database, including 777,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70583 hom., cov: 31)
  • Exomes 𝑓: 0.99 (706709 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.69
• 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=-0.86).
• BP6: Variant 4-78470102-T-C is Benign according to our data. Variant chr4-78470102-T-C is described in ClinVar as Benign. ClinVar VariationId is 261814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.7371+11T>C		intron_variant	Intron 51 of 73	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.7371+11T>C		intron_variant	Intron 51 of 73	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.7371+11T>C		intron_variant	Intron 51 of 63			ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.962 AC: 146270 AN: 152116 Hom.: 70531 Cov.: 31

Gnomad AFR AF: 0.871

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.982

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.974

GnomAD2 exomes AF: 0.988 AC: 239608 AN: 242414 AF XY: 0.991

Gnomad AFR exome AF: 0.862

Gnomad AMR exome AF: 0.989

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.995 AC: 1420475 AN: 1428188 Hom.: 706709 Cov.: 23 AF XY: 0.995 AC XY: 708644 AN XY: 712026

African (AFR) AF: 0.863 AC: 28298 AN: 32794

American (AMR) AF: 0.987 AC: 43636 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 25500 AN: 25788

East Asian (EAS) AF: 1.00 AC: 39249 AN: 39250

South Asian (SAS) AF: 0.999 AC: 84453 AN: 84506

European-Finnish (FIN) AF: 1.00 AC: 53173 AN: 53174

Middle Eastern (MID) AF: 0.986 AC: 5617 AN: 5694

European-Non Finnish (NFE) AF: 0.999 AC: 1082013 AN: 1083516

Other (OTH) AF: 0.988 AC: 58536 AN: 59262

GnomAD4 genome AF: 0.962 AC: 146381 AN: 152234 Hom.: 70583 Cov.: 31 AF XY: 0.963 AC XY: 71629 AN XY: 74418

African (AFR) AF: 0.871 AC: 36145 AN: 41502

American (AMR) AF: 0.982 AC: 15032 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 3442 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 1.00 AC: 4813 AN: 4814

European-Finnish (FIN) AF: 1.00 AC: 10608 AN: 10610

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67909 AN: 68036

Other (OTH) AF: 0.974 AC: 2057 AN: 2112

Alfa AF: 0.969 Hom.: 21819

Bravo AF: 0.955

Asia WGS AF: 0.990 AC: 3442 AN: 3476

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 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. -

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	-0.86
CADD	Benign	0.072
DANN	Benign	0.33
PhyloP100		-1.7
Mutation Taster		=100/0	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: rs7664505; hg19: chr4-79391256;