rs111554790

chr4-78372804-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_025074.7(FRAS1):c.2956G>A(p.Ala986Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,613,102 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A986A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (4 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.24

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013724059).
• BP6: Variant 4-78372804-G-A is Benign according to our data. Variant chr4-78372804-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445365.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000926 (141/152308) while in subpopulation AFR AF= 0.00289 (120/41560). AF 95% confidence interval is 0.00247. There are 2 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.2956G>A	p.Ala986Thr	missense_variant	24/74	ENST00000512123.4
FRAS1	NM_001166133.2	c.2956G>A	p.Ala986Thr	missense_variant	24/42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.2956G>A	p.Ala986Thr	missense_variant	24/74	5	NM_025074.7	P1
FRAS1	ENST00000325942.11	c.2956G>A	p.Ala986Thr	missense_variant	24/42	1
FRAS1	ENST00000682513.1	c.2956G>A	p.Ala986Thr	missense_variant	24/64
FRAS1	ENST00000684159.1	c.2956G>A	p.Ala986Thr	missense_variant	24/45

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 134 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000290 AC: 72 AN: 248700 Hom.: 0 AF XY: 0.000222 AC XY: 30 AN XY: 134900

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1460794 Hom.: 4 Cov.: 31 AF XY: 0.000224 AC XY: 163 AN XY: 726690

Gnomad4 AFR exome AF: 0.00406

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74484

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.00114

ESP6500AA AF: 0.00298 AC: 12

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000356 AC: 43

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FRAS1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Fraser syndrome 1 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	9.1
Dann	Benign	0.18
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.13
Sift	Benign	0.49	T;.
Sift4G	Benign	0.22	T;T
Vest4		0.11
MVP		0.39
ClinPred		0.0036	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.15

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: rs111554790; hg19: chr4-79293958;