NM_013390.3:c.3674G>A

Variant names:

• chr9-71694531-C-T
• rs146520330
• NM_013390.3:c.3674G>A

Variant summary

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

The NM_013390.3(CEMIP2):​c.3674G>A​(p.Arg1225His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R1225C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: CEMIP2 NM_013390.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.376
• Publications: 0 publications found

Genes affected

CEMIP2 (HGNC:11869): (cell migration inducing hyaluronidase 2) This gene encodes a type II transmembrane protein that belongs to the interferon-induced transmembrane (IFITM) protein superfamily. The encoded protein functions as a cell surface hyaluronidase that cleaves extracellular high molecular weight hyaluronan into intermediate size fragments before internalization and degradation in the lysosome. It also has an interferon-mediated antiviral function in humans through activation of the JAK STAT signaling pathway. The activation of this gene by transcription factor SOX4 in breast cancer cells has been shown to mediate the pathological effects of SOX4 on cancer progression. Naturally occurring mutations in this gene are associated with autosomal recessive non-syndromic hearing loss. [provided by RefSeq, Mar 2017]

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=0.074349344).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013390.3. 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
	CEMIP2	NM_013390.3	MANE Select	c.3674G>A	p.Arg1225His	missense	Exon 21 of 24	NP_037522.1	Q9UHN6-1
	CEMIP2	NM_001135820.2		c.3485G>A	p.Arg1162His	missense	Exon 20 of 23	NP_001129292.1	Q9UHN6-2
	CEMIP2	NM_001349784.2		c.1760G>A	p.Arg587His	missense	Exon 21 of 24	NP_001336713.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEMIP2	ENST00000377044.9	TSL:1 MANE Select	c.3674G>A	p.Arg1225His	missense	Exon 21 of 24	ENSP00000366243.4	Q9UHN6-1
	CEMIP2	ENST00000377066.9	TSL:1	c.3485G>A	p.Arg1162His	missense	Exon 20 of 23	ENSP00000366266.5	Q9UHN6-2
	CEMIP2	ENST00000542935.5	TSL:1	n.*1897G>A		non_coding_transcript_exon	Exon 21 of 24	ENSP00000437750.1	F5H6B2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251254 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461550 Hom.: 0 Cov.: 30 AF XY: 0.0000426 AC XY: 31 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000671 AC: 3 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111782

Other (OTH) AF: 0.0000497 AC: 3 AN: 60376

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	0.072
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.82	T
PhyloP100		0.38
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.17
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		0.028	B
Vest4		0.20
MVP		0.51
MPC		0.21
ClinPred		0.067	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.42
Mutation Taster		=88/12	polymorphism

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: rs146520330; hg19: chr9-74309447;