rs7684722

Variant names:

• chr4-78466310-A-G
• rs7684722
• NM_025074.7:c.7132A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-78466310-A-G
• chr4-78466310-A-T
• chr4-78466310-A-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.7132A>G​(p.Lys2378Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,613,966 control chromosomes in the GnomAD database, including 797,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (72262 hom., cov: 31)
  • Exomes 𝑓: 1.0 (724937 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.76
• Publications: 26 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=1.345344E-6).
• BP6: Variant 4-78466310-A-G is Benign according to our data. Variant chr4-78466310-A-G is described in ClinVar as Benign. ClinVar VariationId is 261813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 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.7132A>G	p.Lys2378Glu	missense	Exon 50 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.7132A>G	p.Lys2378Glu	missense	Exon 50 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000682513.1		c.7132A>G	p.Lys2378Glu	missense	Exon 50 of 64	ENSP00000508201.1	A0A804HL50
	FRAS1	ENST00000915768.1		c.7029+1727A>G		intron	N/A	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.974 AC: 148148 AN: 152168 Hom.: 72207 Cov.: 31

Gnomad AFR AF: 0.913

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.982

GnomAD2 exomes AF: 0.991 AC: 247031 AN: 249202 AF XY: 0.993

Gnomad AFR exome AF: 0.904

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.989

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.996 AC: 1455619 AN: 1461680 Hom.: 724937 Cov.: 54 AF XY: 0.996 AC XY: 724433 AN XY: 727120

African (AFR) AF: 0.908 AC: 30383 AN: 33476

American (AMR) AF: 0.989 AC: 44235 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 25844 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39696 AN: 39696

South Asian (SAS) AF: 1.00 AC: 86243 AN: 86254

European-Finnish (FIN) AF: 1.00 AC: 53401 AN: 53402

Middle Eastern (MID) AF: 0.988 AC: 5695 AN: 5766

European-Non Finnish (NFE) AF: 0.999 AC: 1110319 AN: 1111854

Other (OTH) AF: 0.991 AC: 59803 AN: 60372

GnomAD4 genome AF: 0.974 AC: 148262 AN: 152286 Hom.: 72262 Cov.: 31 AF XY: 0.974 AC XY: 72537 AN XY: 74464

African (AFR) AF: 0.913 AC: 37949 AN: 41546

American (AMR) AF: 0.985 AC: 15071 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 3438 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 1.00 AC: 4815 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10616

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67922 AN: 68042

Other (OTH) AF: 0.982 AC: 2078 AN: 2116

Alfa AF: 0.991 Hom.: 215845

Bravo AF: 0.969

TwinsUK AF: 0.998 AC: 3702

ALSPAC AF: 0.998 AC: 3847

ESP6500AA AF: 0.915 AC: 3940

ESP6500EA AF: 0.997 AC: 8493

ExAC AF: 0.990 AC: 119892

Asia WGS AF: 0.993 AC: 3453 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.072	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.2	N
PhyloP100		7.8
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.74	T
Vest4		0.034
ClinPred		0.026	T
GERP RS		5.5
gMVP		0.19
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs7684722; hg19: chr4-79387464; COSMIC: COSV107294965;