4-78317495-T-C

Variant names:

• chr4-78317495-T-C
• rs345514
• NM_025074.7:c.1947T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.1947T>C​(p.His649His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,612,350 control chromosomes in the GnomAD database, including 467,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46225 hom., cov: 32)
  • Exomes 𝑓: 0.76 (421402 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.44
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.007).
• BP6: Variant 4-78317495-T-C is Benign according to our data. Variant chr4-78317495-T-C is described in ClinVar as Benign. ClinVar VariationId is 194790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.841 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.1947T>C	p.His649His	synonymous	Exon 17 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.1947T>C	p.His649His	synonymous	Exon 17 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.1947T>C	p.His649His	synonymous	Exon 17 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.1947T>C	p.His649His	synonymous	Exon 17 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000508900.2	TSL:1	c.1947T>C	p.His649His	synonymous	Exon 17 of 20	ENSP00000423809.2	Q86XX4-6

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118084 AN: 152034 Hom.: 46182 Cov.: 32

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.739 AC: 183163 AN: 247960 AF XY: 0.729

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.688

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.758 AC: 1106463 AN: 1460198 Hom.: 421402 Cov.: 43 AF XY: 0.752 AC XY: 546575 AN XY: 726390

African (AFR) AF: 0.846 AC: 28322 AN: 33460

American (AMR) AF: 0.720 AC: 32103 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 17720 AN: 26118

East Asian (EAS) AF: 0.712 AC: 28252 AN: 39662

South Asian (SAS) AF: 0.597 AC: 51408 AN: 86040

European-Finnish (FIN) AF: 0.808 AC: 42917 AN: 53128

Middle Eastern (MID) AF: 0.645 AC: 3717 AN: 5766

European-Non Finnish (NFE) AF: 0.772 AC: 857292 AN: 1111116

Other (OTH) AF: 0.741 AC: 44732 AN: 60340

GnomAD4 genome AF: 0.777 AC: 118192 AN: 152152 Hom.: 46225 Cov.: 32 AF XY: 0.772 AC XY: 57385 AN XY: 74362

African (AFR) AF: 0.848 AC: 35232 AN: 41536

American (AMR) AF: 0.724 AC: 11065 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2326 AN: 3468

East Asian (EAS) AF: 0.685 AC: 3545 AN: 5174

South Asian (SAS) AF: 0.595 AC: 2858 AN: 4804

European-Finnish (FIN) AF: 0.797 AC: 8431 AN: 10582

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.768 AC: 52240 AN: 67982

Other (OTH) AF: 0.742 AC: 1565 AN: 2108

Alfa AF: 0.761 Hom.: 137326

Bravo AF: 0.777

Asia WGS AF: 0.635 AC: 2208 AN: 3478

EpiCase AF: 0.748

EpiControl AF: 0.750

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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0070
DANN	Benign	0.33
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs345514; hg19: chr4-79238649; COSMIC: COSV53630314;