chr4-78516024-C-T

Position:

• chr4-78516024-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.10389+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,604,770 control chromosomes in the GnomAD database, including 29,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1784 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27535 hom.)
• Consequence: FRAS1 NM_025074.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.728

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=-0.84).
• BP6: Variant 4-78516024-C-T is Benign according to our data. Variant chr4-78516024-C-T is described in ClinVar as [Benign]. Clinvar id is 261796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78516024-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.10389+11C>T		intron_variant		ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10389+11C>T		intron_variant		5	NM_025074.7	ENSP00000422834	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21245 AN: 152028 Hom.: 1784 Cov.: 32

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.138 AC: 32581 AN: 236748 Hom.: 2856 AF XY: 0.137 AC XY: 17647 AN XY: 128354

Gnomad AFR exome AF: 0.0757

Gnomad AMR exome AF: 0.0782

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00171

Gnomad SAS exome AF: 0.0588

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.185 AC: 268299 AN: 1452624 Hom.: 27535 Cov.: 30 AF XY: 0.181 AC XY: 130459 AN XY: 722146

Gnomad4 AFR exome AF: 0.0745

Gnomad4 AMR exome AF: 0.0827

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.00208

Gnomad4 SAS exome AF: 0.0586

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.140 AC: 21245 AN: 152146 Hom.: 1784 Cov.: 32 AF XY: 0.135 AC XY: 10015 AN XY: 74388

Gnomad4 AFR AF: 0.0781

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0533

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.132

Alfa AF: 0.132 Hom.: 509

Bravo AF: 0.135

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.84
CADD	Benign	4.2
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs74632598; hg19: chr4-79437178;