9-14842660-C-G

Variant names:

• chr9-14842660-C-G
• rs41298151
• NM_001379081.2:c.1394G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_144966.7(FREM1):​c.1394G>C​(p.Gly465Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0127 in 1,610,642 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (24 hom., cov: 33)
  • Exomes 𝑓: 0.013 (274 hom.)
• Consequence: FREM1 NM_144966.7 missense, splice_region
• Scores: Splicing: ADA: 0.7675
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.69
• Publications: 13 publications found

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]

FREM1 Gene-Disease associations (from GenCC):

• oculotrichoanal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• BNAR syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• isolated trigonocephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• trigonocephaly 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007178992).
• BP6: Variant 9-14842660-C-G is Benign according to our data. Variant chr9-14842660-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218939.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.012 (1829/152294) while in subpopulation SAS AF = 0.0435 (210/4830). AF 95% confidence interval is 0.0387. There are 24 homozygotes in GnomAd4. There are 947 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144966.7. 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
	FREM1	NM_001379081.2	MANE Select	c.1394G>C	p.Gly465Ala	missense splice_region	Exon 9 of 37	NP_001366010.1
	FREM1	NM_144966.7		c.1394G>C	p.Gly465Ala	missense splice_region	Exon 10 of 38	NP_659403.4
	FREM1	NR_163238.2		n.2210G>C		splice_region non_coding_transcript_exon	Exon 10 of 31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FREM1	ENST00000380880.4	TSL:5 MANE Select	c.1394G>C	p.Gly465Ala	missense splice_region	Exon 9 of 37	ENSP00000370262.3
	FREM1	ENST00000380875.7	TSL:1	n.1394G>C		splice_region non_coding_transcript_exon	Exon 10 of 31	ENSP00000370257.3
	FREM1	ENST00000895028.1		c.1394G>C	p.Gly465Ala	missense splice_region	Exon 9 of 37	ENSP00000565087.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1817 AN: 152176 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00953

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0191 AC: 4667 AN: 244410 AF XY: 0.0196

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0425

Gnomad ASJ exome AF: 0.00202

Gnomad EAS exome AF: 0.0181

Gnomad FIN exome AF: 0.000914

Gnomad NFE exome AF: 0.00981

Gnomad OTH exome AF: 0.0177

GnomAD4 exome AF: 0.0128 AC: 18629 AN: 1458348 Hom.: 274 Cov.: 31 AF XY: 0.0137 AC XY: 9945 AN XY: 725328

African (AFR) AF: 0.0119 AC: 399 AN: 33438

American (AMR) AF: 0.0401 AC: 1793 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 54 AN: 26022

East Asian (EAS) AF: 0.0165 AC: 656 AN: 39680

South Asian (SAS) AF: 0.0475 AC: 4082 AN: 86016

European-Finnish (FIN) AF: 0.000985 AC: 52 AN: 52806

Middle Eastern (MID) AF: 0.0290 AC: 164 AN: 5646

European-Non Finnish (NFE) AF: 0.00949 AC: 10528 AN: 1109800

Other (OTH) AF: 0.0150 AC: 901 AN: 60260

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152294 Hom.: 24 Cov.: 33 AF XY: 0.0127 AC XY: 947 AN XY: 74482

African (AFR) AF: 0.0109 AC: 455 AN: 41558

American (AMR) AF: 0.0192 AC: 294 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5186

South Asian (SAS) AF: 0.0435 AC: 210 AN: 4830

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00953 AC: 648 AN: 68016

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0120 Hom.: 60

Bravo AF: 0.0135

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.0103 AC: 43

ESP6500EA AF: 0.00971 AC: 82

ExAC AF: 0.0181 AC: 2193

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Congenital diaphragmatic hernia (1)
-	-	1	not specified (1)
-	-	1	Oculotrichoanal syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.57
ClinPred		0.034	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.71
Mutation Taster		=59/41	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.77
dbscSNV1_RF	Benign	0.58
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

Other links and lift over

dbSNP: rs41298151; hg19: chr9-14842658; COSMIC: COSV66524407;