rs61748814

chr4-78540802-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025074.7(FRAS1):c.11717T>C(p.Ile3906Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0178 in 1,613,872 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/14 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. I3906I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (18 hom., cov: 32)
  • Exomes 𝑓: 0.018 (284 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.12

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007147819).
• BP6: Variant 4-78540802-T-C is Benign according to our data. Variant chr4-78540802-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547870.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr4-78540802-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0138 (2100/152318) while in subpopulation NFE AF= 0.0213 (1447/68022). AF 95% confidence interval is 0.0204. There are 18 homozygotes in gnomad4. There are 1007 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.11717T>C	p.Ile3906Thr	missense_variant	74/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.11717T>C	p.Ile3906Thr	missense_variant	74/74	5	NM_025074.7	P1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2101 AN: 152200 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00357

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0134

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0135 AC: 3366 AN: 249138 Hom.: 32 AF XY: 0.0140 AC XY: 1896 AN XY: 135170

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00699

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0183 AC: 26707 AN: 1461554 Hom.: 284 Cov.: 31 AF XY: 0.0180 AC XY: 13097 AN XY: 727038

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00820

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.0209

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0138 AC: 2100 AN: 152318 Hom.: 18 Cov.: 32 AF XY: 0.0135 AC XY: 1007 AN XY: 74488

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0134

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0193 Hom.: 56

Bravo AF: 0.0145

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.00402 AC: 16

ESP6500EA AF: 0.0185 AC: 155

ExAC AF: 0.0132 AC: 1593

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0228

EpiControl AF: 0.0200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Fraser syndrome 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2024	BA1, BS2, BP4 -
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	-0.34	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	19
Dann	Benign	0.96
Eigen	Benign	0.031
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
Sift4G	Uncertain	0.0070	D
Vest4		0.21
ClinPred		0.042	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.26

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: rs61748814; hg19: chr4-79461956;