4-78516024-C-T

Variant names:

• chr4-78516024-C-T
• rs74632598
• NM_025074.7:c.10389+11C>T

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.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
• Publications: 5 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=-0.84).
• 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.
• 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 rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.10389+11C>T		intron_variant	Intron 66 of 73	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10389+11C>T		intron_variant	Intron 66 of 73	5	NM_025074.7	ENSP00000422834.2

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

GnomAD2 exomes AF: 0.138 AC: 32581 AN: 236748 AF XY: 0.137

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 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

African (AFR) AF: 0.0745 AC: 2477 AN: 33264

American (AMR) AF: 0.0827 AC: 3604 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2950 AN: 25938

East Asian (EAS) AF: 0.00208 AC: 82 AN: 39392

South Asian (SAS) AF: 0.0586 AC: 4998 AN: 85226

European-Finnish (FIN) AF: 0.156 AC: 8263 AN: 53092

Middle Eastern (MID) AF: 0.0947 AC: 543 AN: 5732

European-Non Finnish (NFE) AF: 0.213 AC: 235679 AN: 1106310

Other (OTH) AF: 0.162 AC: 9703 AN: 60070

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

African (AFR) AF: 0.0781 AC: 3243 AN: 41506

American (AMR) AF: 0.116 AC: 1778 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3470

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5186

South Asian (SAS) AF: 0.0533 AC: 256 AN: 4802

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10586

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13585 AN: 67994

Other (OTH) AF: 0.132 AC: 279 AN: 2114

Alfa AF: 0.132 Hom.: 512

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

-

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.2
DANN	Benign	0.49
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs74632598; hg19: chr4-79437178;