rs12512164

Positions:

• chr4-78379839-G-A
• chr4-78379839-G-C

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.3406G>A​(p.Glu1136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,613,212 control chromosomes in the GnomAD database, including 57,385 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (4821 hom., cov: 32)
  • Exomes 𝑓: 0.26 (52564 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.31

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 (MetaRNN=0.005619079).
• BP6: Variant 4-78379839-G-A is Benign according to our data. Variant chr4-78379839-G-A is described in ClinVar as [Benign]. Clinvar id is 196042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78379839-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.3406G>A	p.Glu1136Lys	missense_variant	27/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.3406G>A	p.Glu1136Lys	missense_variant	27/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.3406G>A	p.Glu1136Lys	missense_variant	27/74	5	NM_025074.7	P1
FRAS1	ENST00000325942.11	c.3406G>A	p.Glu1136Lys	missense_variant	27/42	1
FRAS1	ENST00000682513.1	c.3406G>A	p.Glu1136Lys	missense_variant	27/64
FRAS1	ENST00000684159.1	c.3406G>A	p.Glu1136Lys	missense_variant	27/45

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36694 AN: 151878 Hom.: 4816 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.264

GnomAD3 exomes AF: 0.269 AC: 66797 AN: 248708 Hom.: 9596 AF XY: 0.263 AC XY: 35506 AN XY: 134920

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.216

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.311

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.265 AC: 386883 AN: 1461216 Hom.: 52564 Cov.: 34 AF XY: 0.263 AC XY: 191152 AN XY: 726904

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.362

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.242 AC: 36720 AN: 151996 Hom.: 4821 Cov.: 32 AF XY: 0.242 AC XY: 17995 AN XY: 74284

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.305

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.266

Alfa AF: 0.269 Hom.: 13825

Bravo AF: 0.241

TwinsUK AF: 0.267 AC: 990

ALSPAC AF: 0.268 AC: 1034

ESP6500AA AF: 0.148 AC: 560

ESP6500EA AF: 0.275 AC: 2256

ExAC AF: 0.264 AC: 31918

Asia WGS AF: 0.202 AC: 708 AN: 3476

EpiCase AF: 0.272

EpiControl AF: 0.269

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2014	- -

Fraser syndrome 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.90
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.27
Sift	Benign	0.29	T;.
Sift4G	Benign	0.75	T;T
Vest4		0.36
ClinPred		0.021	T
GERP RS		3.5
gMVP		0.47

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: rs12512164; hg19: chr4-79300993; COSMIC: COSV53590059; COSMIC: COSV53590059;