rs3821169

Variant names:

• chr2-36356318-G-T
• rs3821169
• NM_016441.3:c.26G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_016441.3(CRIM1):​c.26G>T​(p.Gly9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,571,398 control chromosomes in the GnomAD database, including 1,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (158 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1587 hom.)
• Consequence: CRIM1 NM_016441.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.05
• Publications: 8 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: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011918247).
• BP6: Variant 2-36356318-G-T is Benign according to our data. Variant chr2-36356318-G-T is described in ClinVar as [Benign]. Clinvar id is 3059689.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRIM1	NM_016441.3	c.26G>T	p.Gly9Val	missense_variant	Exon 1 of 17	ENST00000280527.7	NP_057525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRIM1	ENST00000280527.7	c.26G>T	p.Gly9Val	missense_variant	Exon 1 of 17	1	NM_016441.3	ENSP00000280527.2
CRIM1	ENST00000426856.1	c.-125G>T		upstream_gene_variant		3		ENSP00000407636.1
CRIM1	ENST00000428774.1	c.-155G>T		upstream_gene_variant		3		ENSP00000415706.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2738 AN: 151966 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00551

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.0493

Gnomad FIN AF: 0.00709

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00915

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0359 AC: 6631 AN: 184938 AF XY: 0.0353

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.0328

Gnomad ASJ exome AF: 0.00592

Gnomad EAS exome AF: 0.243

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00980

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0190 AC: 26907 AN: 1419314 Hom.: 1587 Cov.: 30 AF XY: 0.0197 AC XY: 13850 AN XY: 702524

African (AFR) AF: 0.00212 AC: 68 AN: 32130

American (AMR) AF: 0.0308 AC: 1241 AN: 40288

Ashkenazi Jewish (ASJ) AF: 0.00553 AC: 136 AN: 24608

East Asian (EAS) AF: 0.266 AC: 10039 AN: 37706

South Asian (SAS) AF: 0.0465 AC: 3728 AN: 80248

European-Finnish (FIN) AF: 0.0120 AC: 574 AN: 48006

Middle Eastern (MID) AF: 0.00934 AC: 38 AN: 4070

European-Non Finnish (NFE) AF: 0.00884 AC: 9664 AN: 1093646

Other (OTH) AF: 0.0242 AC: 1419 AN: 58612

GnomAD4 genome AF: 0.0180 AC: 2739 AN: 152084 Hom.: 158 Cov.: 32 AF XY: 0.0196 AC XY: 1459 AN XY: 74354

African (AFR) AF: 0.00296 AC: 123 AN: 41546

American (AMR) AF: 0.0216 AC: 330 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 26 AN: 3464

East Asian (EAS) AF: 0.249 AC: 1276 AN: 5134

South Asian (SAS) AF: 0.0493 AC: 238 AN: 4828

European-Finnish (FIN) AF: 0.00709 AC: 75 AN: 10574

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00915 AC: 622 AN: 67942

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0103 Hom.: 14

Bravo AF: 0.0187

ESP6500AA AF: 0.00125 AC: 5

ESP6500EA AF: 0.00633 AC: 51

ExAC AF: 0.0297 AC: 3478

Asia WGS AF: 0.129 AC: 448 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CRIM1-related disorder Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.22	N
REVEL	Benign	0.082
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0060	B
Vest4		0.19
MPC		0.97
ClinPred		0.025	T
GERP RS		0.45
PromoterAI		0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
gMVP		0.33
Mutation Taster		=89/11	polymorphism (auto)

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: rs3821169; hg19: chr2-36583461; COSMIC: COSV107248012; COSMIC: COSV107248012;