4-78513531-T-G

Variant names:

• chr4-78513531-T-G
• rs35933858
• NM_025074.7:c.10153T>G

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.10153T>G​(p.Tyr3385Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,612,772 control chromosomes in the GnomAD database, including 29,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1791 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27660 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79
• Publications: 21 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 (MetaRNN=0.0010724366).
• BP6: Variant 4-78513531-T-G is Benign according to our data. Variant chr4-78513531-T-G is described in ClinVar as Benign. ClinVar VariationId is 261794.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.10153T>G	p.Tyr3385Asp	missense	Exon 65 of 74	NP_079350.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.10153T>G	p.Tyr3385Asp	missense	Exon 65 of 74	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21326 AN: 152076 Hom.: 1791 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.136 AC: 33756 AN: 248652 AF XY: 0.136

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00167

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.184 AC: 269109 AN: 1460578 Hom.: 27660 Cov.: 33 AF XY: 0.180 AC XY: 130942 AN XY: 726654

African (AFR) AF: 0.0768 AC: 2571 AN: 33472

American (AMR) AF: 0.0819 AC: 3664 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2975 AN: 26132

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39698

South Asian (SAS) AF: 0.0583 AC: 5031 AN: 86240

European-Finnish (FIN) AF: 0.155 AC: 8253 AN: 53218

Middle Eastern (MID) AF: 0.0949 AC: 547 AN: 5764

European-Non Finnish (NFE) AF: 0.213 AC: 236255 AN: 1110994

Other (OTH) AF: 0.161 AC: 9731 AN: 60346

GnomAD4 genome AF: 0.140 AC: 21326 AN: 152194 Hom.: 1791 Cov.: 32 AF XY: 0.135 AC XY: 10063 AN XY: 74406

African (AFR) AF: 0.0801 AC: 3327 AN: 41536

American (AMR) AF: 0.116 AC: 1775 AN: 15284

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

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

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4818

European-Finnish (FIN) AF: 0.147 AC: 1561 AN: 10596

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

European-Non Finnish (NFE) AF: 0.200 AC: 13580 AN: 67986

Other (OTH) AF: 0.134 AC: 282 AN: 2112

Alfa AF: 0.171 Hom.: 5165

Bravo AF: 0.136

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.217 AC: 835

ESP6500AA AF: 0.0765 AC: 308

ESP6500EA AF: 0.196 AC: 1636

ExAC AF: 0.138 AC: 16703

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.187

EpiControl AF: 0.193

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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 13, 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.64
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.8
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.31	T
Vest4		0.16
ClinPred		0.0011	T
GERP RS		3.6
gMVP		0.37
Mutation Taster		=98/2	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: rs35933858; hg19: chr4-79434685; COSMIC: COSV107294966;