chr4-78387426-G-T

Variant names:

• chr4-78387426-G-T
• rs199940702
• NM_025074.7:c.3700G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025074.7(FRAS1):​c.3700G>T​(p.Ala1234Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1234T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2802765).

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.3700G>T	p.Ala1234Ser	missense	Exon 29 of 74	NP_079350.5
	FRAS1	NM_001166133.2		c.3700G>T	p.Ala1234Ser	missense	Exon 29 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.3700G>T	p.Ala1234Ser	missense	Exon 29 of 74	ENSP00000422834.2	Q86XX4-2
	FRAS1	ENST00000325942.11	TSL:1	c.3700G>T	p.Ala1234Ser	missense	Exon 29 of 42	ENSP00000326330.6	Q86XX4-5
	FRAS1	ENST00000915768.1		c.3700G>T	p.Ala1234Ser	missense	Exon 29 of 73	ENSP00000585827.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461344 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726946

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Uncertain	0.98
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.064
Sift	Benign	0.16	T
Sift4G	Benign	0.11	T
Vest4		0.098
MutPred		0.72		Gain of disorder (P = 0.0262)
MVP		0.54
ClinPred		0.29	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.25
Mutation Taster		=76/24	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: rs199940702; hg19: chr4-79308580;