NM_025074.7:c.3406G>A

Variant names:

• chr4-78379839-G-A
• rs12512164
• NM_025074.7:c.3406G>A

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.3406G>A​(p.Glu1136Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,613,212 control chromosomes in the GnomAD database, including 57,385 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4821 hom., cov: 32)
  • Exomes 𝑓: 0.26 (52564 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.31
• Publications: 34 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=0.005619079).
• BP6: Variant 4-78379839-G-A is Benign according to our data. Variant chr4-78379839-G-A is described in ClinVar as Benign. ClinVar VariationId is 196042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.298 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.3406G>A	p.Glu1136Lys	missense	Exon 27 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.3406G>A	p.Glu1136Lys	missense	Exon 27 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.3406G>A	p.Glu1136Lys	missense	Exon 27 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.3406G>A	p.Glu1136Lys	missense	Exon 27 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000915768.1		c.3406G>A	p.Glu1136Lys	missense	Exon 27 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36694 AN: 151878 Hom.: 4816 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.269 AC: 66797 AN: 248708 AF XY: 0.263

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.216

Gnomad FIN exome AF: 0.311

Gnomad NFE exome AF: 0.279

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.265 AC: 386883 AN: 1461216 Hom.: 52564 Cov.: 34 AF XY: 0.263 AC XY: 191152 AN XY: 726904

African (AFR) AF: 0.143 AC: 4793 AN: 33472

American (AMR) AF: 0.362 AC: 16171 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6874 AN: 26128

East Asian (EAS) AF: 0.216 AC: 8584 AN: 39694

South Asian (SAS) AF: 0.189 AC: 16286 AN: 86240

European-Finnish (FIN) AF: 0.315 AC: 16800 AN: 53386

Middle Eastern (MID) AF: 0.233 AC: 1342 AN: 5760

European-Non Finnish (NFE) AF: 0.271 AC: 300920 AN: 1111486

Other (OTH) AF: 0.250 AC: 15113 AN: 60370

GnomAD4 genome AF: 0.242 AC: 36720 AN: 151996 Hom.: 4821 Cov.: 32 AF XY: 0.242 AC XY: 17995 AN XY: 74284

African (AFR) AF: 0.146 AC: 6059 AN: 41466

American (AMR) AF: 0.305 AC: 4658 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 927 AN: 3466

East Asian (EAS) AF: 0.207 AC: 1065 AN: 5148

South Asian (SAS) AF: 0.196 AC: 942 AN: 4810

European-Finnish (FIN) AF: 0.314 AC: 3316 AN: 10554

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18858 AN: 67958

Other (OTH) AF: 0.266 AC: 561 AN: 2112

Alfa AF: 0.264 Hom.: 18888

Bravo AF: 0.241

TwinsUK AF: 0.267 AC: 990

ALSPAC AF: 0.268 AC: 1034

ESP6500AA AF: 0.148 AC: 560

ESP6500EA AF: 0.275 AC: 2256

ExAC AF: 0.264 AC: 31918

Asia WGS AF: 0.202 AC: 708 AN: 3476

EpiCase AF: 0.272

EpiControl AF: 0.269

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.90
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.29	T
Sift4G	Benign	0.75	T
Vest4		0.36
ClinPred		0.021	T
GERP RS		3.5
gMVP		0.47
Mutation Taster		=87/13	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: rs12512164; hg19: chr4-79300993; COSMIC: COSV53590059; COSMIC: COSV53590059;