rs7023244

Variant names:

• chr9-14819372-G-A
• NM_001379081.2:c.2408C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-14819372-G-A
• chr9-14819372-G-C
• chr9-14819372-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001379081.2(FREM1):​c.2408C>T​(p.Ser803Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S803Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FREM1 NM_001379081.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.51

Genes affected

FREM1 (HGNC:23399): (FRAS1 related extracellular matrix 1) This gene encodes a basement membrane protein that may play a role in craniofacial and renal development. Mutations in this gene have been associated with bifid nose with or without anorectal and renal anomalies. Alternatively spliced transcript variants encoding different isoforms have been described. PubMed ID 19940113 describes one such variant that initiates transcription within a distinct, internal exon; the resulting shorter isoform (named Toll-like/interleukin-1 receptor regulator, TILRR) is suggested to be a co-receptor of the interleukin 1 receptor family and may regulate receptor function and Toll-like receptor/interleukin 1 receptor signal transduction, contributing to the control of inflammatory response activation. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FREM1	NM_001379081.2	c.2408C>T	p.Ser803Phe	missense_variant	Exon 14 of 37	ENST00000380880.4	NP_001366010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FREM1	ENST00000380880.4	c.2408C>T	p.Ser803Phe	missense_variant	Exon 14 of 37	5	NM_001379081.2	ENSP00000370262.3
FREM1	ENST00000380875.7	n.2408C>T		non_coding_transcript_exon_variant	Exon 15 of 31	1		ENSP00000370257.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461086 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Oculotrichoanal syndrome;C2750433:BNAR syndrome;C3280974:Trigonocephaly 2 Uncertain:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;D
Vest4		0.67
MutPred		0.39		Loss of disorder (P = 0.0531);Loss of disorder (P = 0.0531);
MVP		0.38
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.39
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-14819370;