chr4-78522683-A-T

Variant names:

• chr4-78522683-A-T
• rs931605
• NM_025074.7:c.10683A>T

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.10683A>T​(p.Glu3561Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,605,288 control chromosomes in the GnomAD database, including 29,222 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 (1781 hom., cov: 32)
  • Exomes 𝑓: 0.18 (27441 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.401
• Publications: 16 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=0.0023269355).
• BP6: Variant 4-78522683-A-T is Benign according to our data. Variant chr4-78522683-A-T is described in ClinVar as Benign. ClinVar VariationId is 261797.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.10683A>T	p.Glu3561Asp	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.10683A>T	p.Glu3561Asp	missense	Exon 69 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.10455A>T	p.Glu3485Asp	missense	Exon 68 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21222 AN: 152052 Hom.: 1781 Cov.: 32

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.135 AC: 32513 AN: 240784 AF XY: 0.135

Gnomad AFR exome AF: 0.0737

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00171

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.184 AC: 266904 AN: 1453118 Hom.: 27441 Cov.: 32 AF XY: 0.180 AC XY: 129775 AN XY: 722410

African (AFR) AF: 0.0740 AC: 2467 AN: 33356

American (AMR) AF: 0.0814 AC: 3582 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2945 AN: 25948

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39570

South Asian (SAS) AF: 0.0582 AC: 4960 AN: 85264

European-Finnish (FIN) AF: 0.155 AC: 8203 AN: 52974

Middle Eastern (MID) AF: 0.0947 AC: 545 AN: 5756

European-Non Finnish (NFE) AF: 0.212 AC: 234465 AN: 1106184

Other (OTH) AF: 0.161 AC: 9655 AN: 60046

GnomAD4 genome AF: 0.139 AC: 21222 AN: 152170 Hom.: 1781 Cov.: 32 AF XY: 0.134 AC XY: 10006 AN XY: 74406

African (AFR) AF: 0.0776 AC: 3217 AN: 41482

American (AMR) AF: 0.116 AC: 1776 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5182

South Asian (SAS) AF: 0.0531 AC: 256 AN: 4822

European-Finnish (FIN) AF: 0.147 AC: 1562 AN: 10598

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

European-Non Finnish (NFE) AF: 0.200 AC: 13584 AN: 68002

Other (OTH) AF: 0.133 AC: 281 AN: 2116

Alfa AF: 0.182 Hom.: 2131

Bravo AF: 0.135

TwinsUK AF: 0.229 AC: 848

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.0776 AC: 290

ESP6500EA AF: 0.197 AC: 1622

ExAC AF: 0.136 AC: 16448

Asia WGS AF: 0.0360 AC: 126 AN: 3478

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	0.055
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.053
DANN	Benign	0.050
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.40
PrimateAI	Benign	0.41	T
Sift4G	Benign	1.0	T
Vest4		0.029
ClinPred		0.0010	T
GERP RS		-1.1
gMVP		0.15
Mutation Taster		=100/0	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: rs931605; hg19: chr4-79443837; COSMIC: COSV107294967;