4-78470102-T-C

Position:

• chr4-78470102-T-C

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.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

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=-0.86).
• BP6: Variant 4-78470102-T-C is Benign according to our data. Variant chr4-78470102-T-C is described in ClinVar as [Benign]. Clinvar id is 261814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78470102-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.7371+11T>C		intron_variant		ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.7371+11T>C		intron_variant		5	NM_025074.7	ENSP00000422834	P1
FRAS1	ENST00000682513.1	c.7371+11T>C		intron_variant				ENSP00000508201

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

GnomAD3 exomes AF: 0.988 AC: 239608 AN: 242414 Hom.: 118535 AF XY: 0.991 AC XY: 130108 AN XY: 131306

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 SAS exome AF: 0.999

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

Gnomad4 AFR exome AF: 0.863

Gnomad4 AMR exome AF: 0.987

Gnomad4 ASJ exome AF: 0.989

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.988

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

Gnomad4 AFR AF: 0.871

Gnomad4 AMR AF: 0.982

Gnomad4 ASJ AF: 0.991

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.974

Alfa AF: 0.970 Hom.: 21523

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

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.072
DANN	Benign	0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs7664505; hg19: chr4-79391256;