rs34670941

Variant names:

• chr4-78526609-T-C
• rs34670941
• NM_025074.7:c.10877T>C

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.10877T>C​(p.Val3626Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,598,906 control chromosomes in the GnomAD database, including 10,137 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 0.13 (1358 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8779 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.371
• Publications: 15 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=0.0020789206).
• BP6: Variant 4-78526609-T-C is Benign according to our data. Variant chr4-78526609-T-C is described in ClinVar as Benign. ClinVar VariationId is 261799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.10877T>C	p.Val3626Ala	missense_variant	Exon 70 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10877T>C	p.Val3626Ala	missense_variant	Exon 70 of 74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19434 AN: 152056 Hom.: 1356 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0972

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.118 AC: 26959 AN: 228754 AF XY: 0.116

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0915

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.0984

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.106 AC: 153208 AN: 1446732 Hom.: 8779 Cov.: 30 AF XY: 0.106 AC XY: 75965 AN XY: 718136

African (AFR) AF: 0.176 AC: 5804 AN: 33042

American (AMR) AF: 0.0936 AC: 4011 AN: 42874

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3448 AN: 25802

East Asian (EAS) AF: 0.209 AC: 8108 AN: 38876

South Asian (SAS) AF: 0.117 AC: 9660 AN: 82628

European-Finnish (FIN) AF: 0.141 AC: 7443 AN: 52738

Middle Eastern (MID) AF: 0.0892 AC: 512 AN: 5738

European-Non Finnish (NFE) AF: 0.0970 AC: 107155 AN: 1105174

Other (OTH) AF: 0.118 AC: 7067 AN: 59860

GnomAD4 genome AF: 0.128 AC: 19446 AN: 152174 Hom.: 1358 Cov.: 33 AF XY: 0.130 AC XY: 9707 AN XY: 74396

African (AFR) AF: 0.170 AC: 7056 AN: 41504

American (AMR) AF: 0.115 AC: 1755 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 464 AN: 3472

East Asian (EAS) AF: 0.233 AC: 1208 AN: 5180

South Asian (SAS) AF: 0.118 AC: 568 AN: 4818

European-Finnish (FIN) AF: 0.134 AC: 1420 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0972 AC: 6610 AN: 67986

Other (OTH) AF: 0.114 AC: 241 AN: 2116

Alfa AF: 0.110 Hom.: 2609

Bravo AF: 0.126

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.0963 AC: 371

ESP6500AA AF: 0.163 AC: 652

ESP6500EA AF: 0.0998 AC: 832

ExAC AF: 0.116 AC: 13940

Asia WGS AF: 0.193 AC: 671 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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.71
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.37
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.27	T
Vest4		0.016
ClinPred		0.0027	T
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20
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: rs34670941; hg19: chr4-79447763; COSMIC: COSV53617197;