4-78432433-C-G

Variant names:

• chr4-78432433-C-G
• rs35219594
• NM_025074.7:c.5046C>G
• FRAS1 p.Asp1682Glu

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025074.7(FRAS1):​c.5046C>G​(p.Asp1682Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,612,766 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (24 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.28
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013111562).
• BP6: Variant 4-78432433-C-G is Benign according to our data. Variant chr4-78432433-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197043.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00319 (486/152318) while in subpopulation NFE AF = 0.00553 (376/68034). AF 95% confidence interval is 0.00507. There are 0 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AD,AR gene

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.5046C>G	p.Asp1682Glu	missense	Exon 38 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.5046C>G	p.Asp1682Glu	missense	Exon 38 of 42	NP_001159605.1	Q86XX4-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.5046C>G	p.Asp1682Glu	missense	Exon 38 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.5046C>G	p.Asp1682Glu	missense	Exon 38 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000915768.1		c.5046C>G	p.Asp1682Glu	missense	Exon 38 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 486 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00375 AC: 927 AN: 246912 AF XY: 0.00330

Gnomad AFR exome AF: 0.000916

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00561

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00485 AC: 7082 AN: 1460448 Hom.: 24 Cov.: 31 AF XY: 0.00475 AC XY: 3449 AN XY: 726354

African (AFR) AF: 0.000867 AC: 29 AN: 33458

American (AMR) AF: 0.00544 AC: 242 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85882

European-Finnish (FIN) AF: 0.00186 AC: 99 AN: 53362

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00580 AC: 6449 AN: 1111350

Other (OTH) AF: 0.00370 AC: 223 AN: 60334

GnomAD4 genome AF: 0.00319 AC: 486 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00295 AC XY: 220 AN XY: 74496

African (AFR) AF: 0.000914 AC: 38 AN: 41566

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00553 AC: 376 AN: 68034

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00430 Hom.: 0

Bravo AF: 0.00366

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Fraser syndrome 1 (2)
-	-	1	FRAS1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.56
Mutation Taster		=63/37	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35219594;

hg19: chr4-79353587;

COSMIC: COSV105111699;