NM_016441.3:c.7T>G

Variant names:

• chr2-36356299-T-G
• rs1668788483
• NM_016441.3:c.7T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016441.3(CRIM1):​c.7T>G​(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CRIM1 NM_016441.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 0 publications found

Genes affected

CRIM1 (HGNC:2359): (cysteine rich transmembrane BMP regulator 1) This gene encodes a transmembrane protein containing six cysteine-rich repeat domains and an insulin-like growth factor-binding domain. The encoded protein may play a role in tissue development though interactions with members of the transforming growth factor beta family, such as bone morphogenetic proteins. [provided by RefSeq, Nov 2010]

CRIM1 Gene-Disease associations (from GenCC):

• colobomatous macrophthalmia-microcornea syndrome

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2610945).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016441.3. 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
	CRIM1	NM_016441.3	MANE Select	c.7T>G	p.Leu3Val	missense	Exon 1 of 17	NP_057525.1	Q9NZV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRIM1	ENST00000280527.7	TSL:1 MANE Select	c.7T>G	p.Leu3Val	missense	Exon 1 of 17	ENSP00000280527.2	Q9NZV1
	CRIM1	ENST00000928039.1		c.7T>G	p.Leu3Val	missense	Exon 1 of 18	ENSP00000598098.1
	CRIM1	ENST00000868088.1		c.7T>G	p.Leu3Val	missense	Exon 1 of 17	ENSP00000538147.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375150 Hom.: 0 Cov.: 26 AF XY: 0.00000148 AC XY: 1 AN XY: 677644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000332 AC: 1 AN: 30160

American (AMR) AF: 0.00 AC: 0 AN: 36194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22710

East Asian (EAS) AF: 0.00 AC: 0 AN: 35902

South Asian (SAS) AF: 0.00 AC: 0 AN: 74948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3912

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068526

Other (OTH) AF: 0.00 AC: 0 AN: 56822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.099
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.077
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.89	P
Vest4		0.28
MutPred		0.23		Gain of catalytic residue at L3 (P = 0.0516)
MVP		0.12
MPC		0.67
ClinPred		0.88	D
GERP RS		1.3
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Varity_R		0.18
gMVP		0.20
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1668788483; hg19: chr2-36583442;