rs148663672

Variant names:

• chr4-78421970-C-T
• rs148663672
• NM_025074.7:c.4648C>T

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.4648C>T​(p.Leu1550Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,613,272 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0045 (14 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 1.95
• Publications: 8 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=0.014880002).
• BP6: Variant 4-78421970-C-T is Benign according to our data. Variant chr4-78421970-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 349715.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00258 (392/152214) while in subpopulation NFE AF = 0.00463 (315/68020). AF 95% confidence interval is 0.00421. There are 1 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR,AD 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.4648C>T	p.Leu1550Phe	missense	Exon 34 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.4648C>T	p.Leu1550Phe	missense	Exon 34 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.4648C>T	p.Leu1550Phe	missense	Exon 34 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.4648C>T	p.Leu1550Phe	missense	Exon 34 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000915768.1		c.4648C>T	p.Leu1550Phe	missense	Exon 34 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152096 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00232 AC: 575 AN: 248184 AF XY: 0.00235

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00446 AC: 6522 AN: 1461058 Hom.: 14 Cov.: 33 AF XY: 0.00421 AC XY: 3060 AN XY: 726786

African (AFR) AF: 0.000508 AC: 17 AN: 33476

American (AMR) AF: 0.00105 AC: 47 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86148

European-Finnish (FIN) AF: 0.00195 AC: 104 AN: 53358

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00556 AC: 6175 AN: 1111466

Other (OTH) AF: 0.00290 AC: 175 AN: 60352

GnomAD4 genome AF: 0.00258 AC: 392 AN: 152214 Hom.: 1 Cov.: 31 AF XY: 0.00226 AC XY: 168 AN XY: 74404

African (AFR) AF: 0.000987 AC: 41 AN: 41548

American (AMR) AF: 0.000850 AC: 13 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00463 AC: 315 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00238

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00146 AC: 6

ESP6500EA AF: 0.00419 AC: 35

ExAC AF: 0.00225 AC: 272

EpiCase AF: 0.00338

EpiControl AF: 0.00327

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	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	Benign	0.22
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.23
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.011	D
Vest4		0.39
MVP		0.81
ClinPred		0.026	T
GERP RS		5.7
gMVP		0.29
Mutation Taster		=73/27	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

Other links and lift over

dbSNP: rs148663672; hg19: chr4-79343124; COSMIC: COSV106090269;