rs931605

Variant names:

• chr4-78522683-A-T
• rs931605
• NM_025074.7:c.10683A>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.10683A>T​(p.Glu3561Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,605,288 control chromosomes in the GnomAD database, including 29,222 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 (1781 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27441 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.401
• Publications: 16 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=0.0023269355).
• BP6: Variant 4-78522683-A-T is Benign according to our data. Variant chr4-78522683-A-T is described in ClinVar as Benign. ClinVar VariationId is 261797.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.10683A>T	p.Glu3561Asp	missense_variant	Exon 69 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10683A>T	p.Glu3561Asp	missense_variant	Exon 69 of 74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21222 AN: 152052 Hom.: 1781 Cov.: 32

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.135 AC: 32513 AN: 240784 AF XY: 0.135

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00171

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.184 AC: 266904 AN: 1453118 Hom.: 27441 Cov.: 32 AF XY: 0.180 AC XY: 129775 AN XY: 722410

African (AFR) AF: 0.0740 AC: 2467 AN: 33356

American (AMR) AF: 0.0814 AC: 3582 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2945 AN: 25948

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39570

South Asian (SAS) AF: 0.0582 AC: 4960 AN: 85264

European-Finnish (FIN) AF: 0.155 AC: 8203 AN: 52974

Middle Eastern (MID) AF: 0.0947 AC: 545 AN: 5756

European-Non Finnish (NFE) AF: 0.212 AC: 234465 AN: 1106184

Other (OTH) AF: 0.161 AC: 9655 AN: 60046

GnomAD4 genome AF: 0.139 AC: 21222 AN: 152170 Hom.: 1781 Cov.: 32 AF XY: 0.134 AC XY: 10006 AN XY: 74406

African (AFR) AF: 0.0776 AC: 3217 AN: 41482

American (AMR) AF: 0.116 AC: 1776 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5182

South Asian (SAS) AF: 0.0531 AC: 256 AN: 4822

European-Finnish (FIN) AF: 0.147 AC: 1562 AN: 10598

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

European-Non Finnish (NFE) AF: 0.200 AC: 13584 AN: 68002

Other (OTH) AF: 0.133 AC: 281 AN: 2116

Alfa AF: 0.182 Hom.: 2131

Bravo AF: 0.135

TwinsUK AF: 0.229 AC: 848

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.0776 AC: 290

ESP6500EA AF: 0.197 AC: 1622

ExAC AF: 0.136 AC: 16448

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 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.053
DANN	Benign	0.050
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.40
PrimateAI	Benign	0.41	T
Sift4G	Benign	1.0	T
Vest4		0.029
ClinPred		0.0010	T
GERP RS		-1.1
gMVP		0.15
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: rs931605; hg19: chr4-79443837; COSMIC: COSV107294967;