4-78513531-T-G

Position:

• chr4-78513531-T-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.10153T>G​(p.Tyr3385Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,612,772 control chromosomes in the GnomAD database, including 29,451 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 0.14 (1791 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27660 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79

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=0.0010724366).
• BP6: Variant 4-78513531-T-G is Benign according to our data. Variant chr4-78513531-T-G is described in ClinVar as [Benign]. Clinvar id is 261794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78513531-T-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.10153T>G	p.Tyr3385Asp	missense_variant	65/74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.10153T>G	p.Tyr3385Asp	missense_variant	65/74	5	NM_025074.7	ENSP00000422834.2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21326 AN: 152076 Hom.: 1791 Cov.: 32

Gnomad AFR AF: 0.0803

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0531

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.136 AC: 33756 AN: 248652 Hom.: 3024 AF XY: 0.136 AC XY: 18298 AN XY: 134898

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00167

Gnomad SAS exome AF: 0.0578

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.184 AC: 269109 AN: 1460578 Hom.: 27660 Cov.: 33 AF XY: 0.180 AC XY: 130942 AN XY: 726654

Gnomad4 AFR exome AF: 0.0768

Gnomad4 AMR exome AF: 0.0819

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.0583

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.140 AC: 21326 AN: 152194 Hom.: 1791 Cov.: 32 AF XY: 0.135 AC XY: 10063 AN XY: 74406

Gnomad4 AFR AF: 0.0801

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.0529

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.134

Alfa AF: 0.180 Hom.: 4016

Bravo AF: 0.136

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.217 AC: 835

ESP6500AA AF: 0.0765 AC: 308

ESP6500EA AF: 0.196 AC: 1636

ExAC AF: 0.138 AC: 16703

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.187

EpiControl AF: 0.193

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

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.64
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.31	T
Vest4		0.16
ClinPred		0.0011	T
GERP RS		3.6
gMVP		0.37

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: rs35933858; hg19: chr4-79434685;