rs76630865

chr4-78499715-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):c.9116-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,611,622 control chromosomes in the GnomAD database, including 25,504 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2557 hom., cov: 33)
  • Exomes 𝑓: 0.18 (22947 hom.)
• Consequence: FRAS1 NM_025074.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0530

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-78499715-C-T is Benign according to our data. Variant chr4-78499715-C-T is described in ClinVar as [Benign]. Clinvar id is 261819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78499715-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.9116-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.9116-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.9116-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27515 AN: 152030 Hom.: 2557 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.177 AC: 44060 AN: 248434 Hom.: 4038 AF XY: 0.176 AC XY: 23785 AN XY: 134766

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.222

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.176 AC: 256763 AN: 1459474 Hom.: 22947 Cov.: 32 AF XY: 0.175 AC XY: 127095 AN XY: 726050

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.251

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.181 AC: 27520 AN: 152148 Hom.: 2557 Cov.: 33 AF XY: 0.182 AC XY: 13528 AN XY: 74378

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.257

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.187

Alfa AF: 0.185 Hom.: 1175

Bravo AF: 0.179

Asia WGS AF: 0.201 AC: 700 AN: 3478

EpiCase AF: 0.184

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Fraser syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.80
Cadd	Benign	2.2
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs76630865; hg19: chr4-79420869;