4-78526609-T-C

Position:

• chr4-78526609-T-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.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. 10/14 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

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=0.0020789206).
• BP6: Variant 4-78526609-T-C is Benign according to our data. Variant chr4-78526609-T-C is described in ClinVar as [Benign]. Clinvar id is 261799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78526609-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.10877T>C	p.Val3626Ala	missense_variant	70/74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10877T>C	p.Val3626Ala	missense_variant	70/74	5	NM_025074.7	ENSP00000422834	P1

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

GnomAD3 exomes AF: 0.118 AC: 26959 AN: 228754 Hom.: 1731 AF XY: 0.116 AC XY: 14308 AN XY: 123364

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 SAS exome AF: 0.115

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

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0936

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.0970

Gnomad4 OTH exome AF: 0.118

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

Gnomad4 AFR AF: 0.170

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.0972

Gnomad4 OTH AF: 0.114

Alfa AF: 0.106 Hom.: 1595

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

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fraser syndrome 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	P
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

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: rs34670941; hg19: chr4-79447763; COSMIC: COSV53617197;