rs4859905

Positions:

• chr4-78066003-A-C
• chr4-78066003-A-G
• chr4-78066003-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025074.7(FRAS1):​c.95A>C​(p.Asp32Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 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. D32G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRAS1 NM_025074.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24660408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRAS1	NM_025074.7	c.95A>C	p.Asp32Ala	missense_variant	2/74	ENST00000512123.4	NP_079350.5
FRAS1	NM_001166133.2	c.95A>C	p.Asp32Ala	missense_variant	2/42		NP_001159605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRAS1	ENST00000512123.4	c.95A>C	p.Asp32Ala	missense_variant	2/74	5	NM_025074.7	ENSP00000422834	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Benign	-0.060
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.64	N;D
REVEL	Benign	0.25
Sift	Benign	0.036	D;D
Sift4G	Benign	0.57	T;T
Vest4		0.34
MutPred		0.55		Loss of glycosylation at S33 (P = 0.0383);Loss of glycosylation at S33 (P = 0.0383);
MVP		0.72
ClinPred		0.58	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4859905; hg19: chr4-78987157;