rs35030041

Positions:

• chr4-78315684-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025074.7(FRAS1):​c.1769T>C​(p.Met590Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,613,980 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.70

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=0.004378438).
• BP6: Variant 4-78315684-T-C is Benign according to our data. Variant chr4-78315684-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 235757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1688/152312) while in subpopulation AFR AF= 0.0374 (1553/41546). AF 95% confidence interval is 0.0358. There are 28 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.1769T>C	p.Met590Thr	missense_variant	16/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.1769T>C	p.Met590Thr	missense_variant	16/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.1769T>C	p.Met590Thr	missense_variant	16/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1671 AN: 152194 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00276 AC: 687 AN: 249228 Hom.: 11 AF XY: 0.00214 AC XY: 289 AN XY: 135206

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00113 AC: 1649 AN: 1461668 Hom.: 17 Cov.: 31 AF XY: 0.000996 AC XY: 724 AN XY: 727118

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.0111 AC: 1688 AN: 152312 Hom.: 28 Cov.: 32 AF XY: 0.0106 AC XY: 786 AN XY: 74496

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00190 Hom.: 10

Bravo AF: 0.0126

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0358 AC: 142

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00330 AC: 399

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely 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	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 28, 2015	- -

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. -

FRAS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.58
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.60	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.16
Sift	Benign	0.036	D;.
Sift4G	Benign	0.36	T;T
Vest4		0.25
MVP		0.58
ClinPred		0.025	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.38

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: rs35030041; hg19: chr4-79236838; COSMIC: COSV99079716;