4-78513531-T-G

Variant names:

• chr4-78513531-T-G
• rs35933858
• NM_025074.7:c.10153T>G

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.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. 12/16 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
• Publications: 21 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=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 VariationId is 261794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.197 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.10153T>G	p.Tyr3385Asp	missense	Exon 65 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.10153T>G	p.Tyr3385Asp	missense	Exon 65 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.9925T>G	p.Tyr3309Asp	missense	Exon 64 of 73	ENSP00000585827.1

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

GnomAD2 exomes AF: 0.136 AC: 33756 AN: 248652 AF XY: 0.136

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 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

African (AFR) AF: 0.0768 AC: 2571 AN: 33472

American (AMR) AF: 0.0819 AC: 3664 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2975 AN: 26132

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39698

South Asian (SAS) AF: 0.0583 AC: 5031 AN: 86240

European-Finnish (FIN) AF: 0.155 AC: 8253 AN: 53218

Middle Eastern (MID) AF: 0.0949 AC: 547 AN: 5764

European-Non Finnish (NFE) AF: 0.213 AC: 236255 AN: 1110994

Other (OTH) AF: 0.161 AC: 9731 AN: 60346

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

African (AFR) AF: 0.0801 AC: 3327 AN: 41536

American (AMR) AF: 0.116 AC: 1775 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3470

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5186

South Asian (SAS) AF: 0.0529 AC: 255 AN: 4818

European-Finnish (FIN) AF: 0.147 AC: 1561 AN: 10596

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13580 AN: 67986

Other (OTH) AF: 0.134 AC: 282 AN: 2112

Alfa AF: 0.171 Hom.: 5165

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
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
PhyloP100		1.8
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.31	T
Vest4		0.16
ClinPred		0.0011	T
GERP RS		3.6
gMVP		0.37
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35933858; hg19: chr4-79434685; COSMIC: COSV107294966;