4-78466310-A-G

Position:

• chr4-78466310-A-G

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.7132A>G​(p.Lys2378Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,613,966 control chromosomes in the GnomAD database, including 797,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72262 hom., cov: 31)
  • Exomes 𝑓: 1.0 (724937 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.76

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=1.345344E-6).
• BP6: Variant 4-78466310-A-G is Benign according to our data. Variant chr4-78466310-A-G is described in ClinVar as [Benign]. Clinvar id is 261813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78466310-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.7132A>G	p.Lys2378Glu	missense_variant	50/74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.7132A>G	p.Lys2378Glu	missense_variant	50/74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.7132A>G	p.Lys2378Glu	missense_variant	50/64			ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148148 AN: 152168 Hom.: 72207 Cov.: 31

Gnomad AFR AF: 0.913

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.982

GnomAD3 exomes AF: 0.991 AC: 247031 AN: 249202 Hom.: 122497 AF XY: 0.993 AC XY: 134218 AN XY: 135158

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.989

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.996 AC: 1455619 AN: 1461680 Hom.: 724937 Cov.: 54 AF XY: 0.996 AC XY: 724433 AN XY: 727120

Gnomad4 AFR exome AF: 0.908

Gnomad4 AMR exome AF: 0.989

Gnomad4 ASJ exome AF: 0.989

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.991

GnomAD4 genome AF: 0.974 AC: 148262 AN: 152286 Hom.: 72262 Cov.: 31 AF XY: 0.974 AC XY: 72537 AN XY: 74464

Gnomad4 AFR AF: 0.913

Gnomad4 AMR AF: 0.985

Gnomad4 ASJ AF: 0.991

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.982

Alfa AF: 0.993 Hom.: 148176

Bravo AF: 0.969

TwinsUK AF: 0.998 AC: 3702

ALSPAC AF: 0.998 AC: 3847

ESP6500AA AF: 0.915 AC: 3940

ESP6500EA AF: 0.997 AC: 8493

ExAC AF: 0.990 AC: 119892

Asia WGS AF: 0.993 AC: 3453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Fraser syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.072	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.74	T
Vest4		0.034
ClinPred		0.026	T
GERP RS		5.5
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs7684722; hg19: chr4-79387464;