rs34670941

Variant names:

• chr4-78526609-T-C
• rs34670941
• NM_025074.7:c.10877T>C

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.10877T>C​(p.Val3626Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,598,906 control chromosomes in the GnomAD database, including 10,137 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 0.13 (1358 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8779 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.371
• Publications: 15 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=0.0020789206).
• BP6: Variant 4-78526609-T-C is Benign according to our data. Variant chr4-78526609-T-C is described in ClinVar as Benign. ClinVar VariationId is 261799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 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.10877T>C	p.Val3626Ala	missense	Exon 70 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.10877T>C	p.Val3626Ala	missense	Exon 70 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000915768.1		c.10649T>C	p.Val3550Ala	missense	Exon 69 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19434 AN: 152056 Hom.: 1356 Cov.: 33

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0972

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.118 AC: 26959 AN: 228754 AF XY: 0.116

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.0915

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.0984

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.106 AC: 153208 AN: 1446732 Hom.: 8779 Cov.: 30 AF XY: 0.106 AC XY: 75965 AN XY: 718136

African (AFR) AF: 0.176 AC: 5804 AN: 33042

American (AMR) AF: 0.0936 AC: 4011 AN: 42874

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3448 AN: 25802

East Asian (EAS) AF: 0.209 AC: 8108 AN: 38876

South Asian (SAS) AF: 0.117 AC: 9660 AN: 82628

European-Finnish (FIN) AF: 0.141 AC: 7443 AN: 52738

Middle Eastern (MID) AF: 0.0892 AC: 512 AN: 5738

European-Non Finnish (NFE) AF: 0.0970 AC: 107155 AN: 1105174

Other (OTH) AF: 0.118 AC: 7067 AN: 59860

GnomAD4 genome AF: 0.128 AC: 19446 AN: 152174 Hom.: 1358 Cov.: 33 AF XY: 0.130 AC XY: 9707 AN XY: 74396

African (AFR) AF: 0.170 AC: 7056 AN: 41504

American (AMR) AF: 0.115 AC: 1755 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 464 AN: 3472

East Asian (EAS) AF: 0.233 AC: 1208 AN: 5180

South Asian (SAS) AF: 0.118 AC: 568 AN: 4818

European-Finnish (FIN) AF: 0.134 AC: 1420 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0972 AC: 6610 AN: 67986

Other (OTH) AF: 0.114 AC: 241 AN: 2116

Alfa AF: 0.110 Hom.: 2609

Bravo AF: 0.126

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.0963 AC: 371

ESP6500AA AF: 0.163 AC: 652

ESP6500EA AF: 0.0998 AC: 832

ExAC AF: 0.116 AC: 13940

Asia WGS AF: 0.193 AC: 671 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.71
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.91	T
PhyloP100		0.37
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.27	T
Vest4		0.016
ClinPred		0.0027	T
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.20
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: rs34670941; hg19: chr4-79447763; COSMIC: COSV53617197;