NM_025074.7:c.6444C>T

Variant names:

• chr4-78450320-C-T
• rs17003235
• NM_025074.7:c.6444C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.6444C>T​(p.Thr2148Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,613,304 control chromosomes in the GnomAD database, including 37,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3651 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34198 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.561
• Publications: 10 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP6: Variant 4-78450320-C-T is Benign according to our data. Variant chr4-78450320-C-T is described in ClinVar as Benign. ClinVar VariationId is 261809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.561 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.6444C>T	p.Thr2148Thr	synonymous_variant	Exon 45 of 74	ENST00000512123.4	NP_079350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.6444C>T	p.Thr2148Thr	synonymous_variant	Exon 45 of 74	5	NM_025074.7	ENSP00000422834.2
FRAS1	ENST00000682513.1	c.6444C>T	p.Thr2148Thr	synonymous_variant	Exon 45 of 64			ENSP00000508201.1
FRAS1	ENST00000684159.1	c.6444C>T	p.Thr2148Thr	synonymous_variant	Exon 45 of 45			ENSP00000506875.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31858 AN: 151920 Hom.: 3653 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0653

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.163 AC: 40697 AN: 249132 AF XY: 0.160

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.00172

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.207 AC: 302420 AN: 1461266 Hom.: 34198 Cov.: 33 AF XY: 0.202 AC XY: 146852 AN XY: 726948

African (AFR) AF: 0.281 AC: 9392 AN: 33450

American (AMR) AF: 0.103 AC: 4601 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3057 AN: 26128

East Asian (EAS) AF: 0.00212 AC: 84 AN: 39696

South Asian (SAS) AF: 0.0738 AC: 6365 AN: 86252

European-Finnish (FIN) AF: 0.170 AC: 9056 AN: 53388

Middle Eastern (MID) AF: 0.116 AC: 670 AN: 5758

European-Non Finnish (NFE) AF: 0.232 AC: 257854 AN: 1111524

Other (OTH) AF: 0.188 AC: 11341 AN: 60360

GnomAD4 genome AF: 0.210 AC: 31872 AN: 152038 Hom.: 3651 Cov.: 32 AF XY: 0.202 AC XY: 15024 AN XY: 74310

African (AFR) AF: 0.277 AC: 11493 AN: 41444

American (AMR) AF: 0.155 AC: 2362 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5170

South Asian (SAS) AF: 0.0654 AC: 315 AN: 4820

European-Finnish (FIN) AF: 0.165 AC: 1740 AN: 10568

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14920 AN: 67972

Other (OTH) AF: 0.193 AC: 407 AN: 2110

Alfa AF: 0.217 Hom.: 2005

Bravo AF: 0.212

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fraser syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.0
DANN	Benign	0.54
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs17003235; hg19: chr4-79371474;