rs12504081

Variant names:

• chr4-78284545-T-A
• rs12504081
• NM_025074.7:c.1396T>A

Your query was ambiguous. Multiple possible variants found:

• chr4-78284545-T-A
• chr4-78284545-T-G

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.1396T>A​(p.Leu466Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,609,308 control chromosomes in the GnomAD database, including 103,537 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8159 hom., cov: 30)
  • Exomes 𝑓: 0.36 (95378 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.71
• Publications: 32 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=0.00140059).
• BP6: Variant 4-78284545-T-A is Benign according to our data. Variant chr4-78284545-T-A is described in ClinVar as Benign. ClinVar VariationId is 261803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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.1396T>A	p.Leu466Ile	missense	Exon 13 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.1396T>A	p.Leu466Ile	missense	Exon 13 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.1396T>A	p.Leu466Ile	missense	Exon 13 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.1396T>A	p.Leu466Ile	missense	Exon 13 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000508900.2	TSL:1	c.1396T>A	p.Leu466Ile	missense	Exon 13 of 20	ENSP00000423809.2	Q86XX4-6

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48337 AN: 151774 Hom.: 8153 Cov.: 30

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.360 AC: 88348 AN: 245648 AF XY: 0.358

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.406

Gnomad NFE exome AF: 0.361

Gnomad OTH exome AF: 0.357

GnomAD4 exome AF: 0.359 AC: 523535 AN: 1457416 Hom.: 95378 Cov.: 35 AF XY: 0.358 AC XY: 259651 AN XY: 724822

African (AFR) AF: 0.191 AC: 6345 AN: 33260

American (AMR) AF: 0.416 AC: 18428 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9771 AN: 26052

East Asian (EAS) AF: 0.385 AC: 15193 AN: 39476

South Asian (SAS) AF: 0.325 AC: 27691 AN: 85300

European-Finnish (FIN) AF: 0.403 AC: 21503 AN: 53374

Middle Eastern (MID) AF: 0.326 AC: 1877 AN: 5756

European-Non Finnish (NFE) AF: 0.362 AC: 402141 AN: 1109692

Other (OTH) AF: 0.342 AC: 20586 AN: 60214

GnomAD4 genome AF: 0.318 AC: 48367 AN: 151892 Hom.: 8159 Cov.: 30 AF XY: 0.322 AC XY: 23879 AN XY: 74216

African (AFR) AF: 0.196 AC: 8132 AN: 41430

American (AMR) AF: 0.377 AC: 5760 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1293 AN: 3468

East Asian (EAS) AF: 0.379 AC: 1951 AN: 5152

South Asian (SAS) AF: 0.330 AC: 1585 AN: 4796

European-Finnish (FIN) AF: 0.401 AC: 4225 AN: 10528

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.359 AC: 24353 AN: 67924

Other (OTH) AF: 0.322 AC: 680 AN: 2110

Alfa AF: 0.312 Hom.: 2462

Bravo AF: 0.314

TwinsUK AF: 0.369 AC: 1368

ALSPAC AF: 0.368 AC: 1417

ESP6500AA AF: 0.186 AC: 762

ESP6500EA AF: 0.348 AC: 2921

ExAC AF: 0.349 AC: 42268

Asia WGS AF: 0.340 AC: 1179 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)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.0051
Eigen_PC	Benign	-0.023
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Uncertain	0.021	D
Vest4		0.27
ClinPred		0.015	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.45
Mutation Taster		=90/10	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: rs12504081; hg19: chr4-79205699; COSMIC: COSV53587279;