chr4-78522696-G-A

Variant names:

• chr4-78522696-G-A
• rs931606
• NM_025074.7:c.10696G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025074.7(FRAS1):​c.10696G>A​(p.Val3566Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,606,372 control chromosomes in the GnomAD database, including 239,713 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20748 hom., cov: 31)
  • Exomes 𝑓: 0.55 (218965 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.46
• Publications: 37 publications found

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]

FRAS1 Gene-Disease associations (from GenCC):

• Fraser syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Fraser syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.3782646E-5).
• BP6: Variant 4-78522696-G-A is Benign according to our data. Variant chr4-78522696-G-A is described in ClinVar as Benign. ClinVar VariationId is 261798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.10696G>A	p.Val3566Ile	missense	Exon 69 of 74	NP_079350.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.10696G>A	p.Val3566Ile	missense	Exon 69 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.10468G>A	p.Val3490Ile	missense	Exon 68 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79152 AN: 151816 Hom.: 20740 Cov.: 31

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.521 AC: 125705 AN: 241368 AF XY: 0.530

Gnomad AFR exome AF: 0.507

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.484

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.547 AC: 794994 AN: 1454438 Hom.: 218965 Cov.: 35 AF XY: 0.548 AC XY: 396481 AN XY: 723208

African (AFR) AF: 0.507 AC: 16899 AN: 33344

American (AMR) AF: 0.435 AC: 19088 AN: 43930

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 14917 AN: 25984

East Asian (EAS) AF: 0.507 AC: 20031 AN: 39532

South Asian (SAS) AF: 0.596 AC: 50872 AN: 85426

European-Finnish (FIN) AF: 0.454 AC: 24077 AN: 52986

Middle Eastern (MID) AF: 0.611 AC: 3518 AN: 5756

European-Non Finnish (NFE) AF: 0.553 AC: 612505 AN: 1107362

Other (OTH) AF: 0.550 AC: 33087 AN: 60118

GnomAD4 genome AF: 0.521 AC: 79204 AN: 151934 Hom.: 20748 Cov.: 31 AF XY: 0.517 AC XY: 38363 AN XY: 74262

African (AFR) AF: 0.510 AC: 21119 AN: 41396

American (AMR) AF: 0.472 AC: 7212 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1950 AN: 3470

East Asian (EAS) AF: 0.491 AC: 2532 AN: 5162

South Asian (SAS) AF: 0.593 AC: 2858 AN: 4818

European-Finnish (FIN) AF: 0.467 AC: 4923 AN: 10550

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36846 AN: 67956

Other (OTH) AF: 0.545 AC: 1147 AN: 2106

Alfa AF: 0.538 Hom.: 87862

Bravo AF: 0.522

TwinsUK AF: 0.559 AC: 2073

ALSPAC AF: 0.558 AC: 2151

ESP6500AA AF: 0.519 AC: 1938

ESP6500EA AF: 0.545 AC: 4480

ExAC AF: 0.519 AC: 62682

Asia WGS AF: 0.502 AC: 1745 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fraser syndrome 1 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.18
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.000044	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.5
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	1.0	T
Vest4		0.026
ClinPred		0.0091	T
GERP RS		4.9
gMVP		0.081
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs931606; hg19: chr4-79443850; COSMIC: COSV53595004;