9-71685395-TAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAA

Variant names:

• chr9-71685395-T-TAAA
• rs36080695
• NM_013390.3:c.3956-5_3956-3dupTTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_013390.3(CEMIP2):​c.3956-5_3956-3dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 0)
  • Exomes 𝑓: 0.039 (34 hom.)
• Consequence: CEMIP2 NM_013390.3 splice_region, intron
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 0.302
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 9-71685395-T-TAAA is Benign according to our data. Variant chr9-71685395-T-TAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1206164.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0234 (2714/116224) while in subpopulation SAS AF = 0.044 (153/3480). AF 95% confidence interval is 0.0383. There are 54 homozygotes in GnomAd4. There are 1232 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEMIP2	NM_013390.3	c.3956-5_3956-3dupTTT		splice_region_variant, intron_variant	Intron 23 of 23	ENST00000377044.9	NP_037522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEMIP2	ENST00000377044.9	c.3956-3_3956-2insTTT		splice_region_variant, intron_variant	Intron 23 of 23	1	NM_013390.3	ENSP00000366243.4

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 2713 AN: 116248 Hom.: 53 Cov.: 0

Gnomad AFR AF: 0.0390

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0315

Gnomad EAS AF: 0.00641

Gnomad SAS AF: 0.0439

Gnomad FIN AF: 0.00852

Gnomad MID AF: 0.0259

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0170

GnomAD2 exomes AF: 0.0430 AC: 763 AN: 17724 AF XY: 0.0453

Gnomad AFR exome AF: 0.0821

Gnomad AMR exome AF: 0.0522

Gnomad ASJ exome AF: 0.0366

Gnomad EAS exome AF: 0.0836

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0276

Gnomad OTH exome AF: 0.0461

GnomAD4 exome AF: 0.0386 AC: 40100 AN: 1039446 Hom.: 34 Cov.: 14 AF XY: 0.0384 AC XY: 19084 AN XY: 496616

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

African (AFR) AF: 0.101 AC: 2157 AN: 21326

American (AMR) AF: 0.0350 AC: 395 AN: 11290

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 419 AN: 14648

East Asian (EAS) AF: 0.0494 AC: 1246 AN: 25224

South Asian (SAS) AF: 0.0627 AC: 1915 AN: 30566

European-Finnish (FIN) AF: 0.0308 AC: 726 AN: 23604

Middle Eastern (MID) AF: 0.0303 AC: 87 AN: 2868

European-Non Finnish (NFE) AF: 0.0363 AC: 31525 AN: 867688

Other (OTH) AF: 0.0386 AC: 1630 AN: 42232

⚠️ 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 AF: 0.0234 AC: 2714 AN: 116224 Hom.: 54 Cov.: 0 AF XY: 0.0228 AC XY: 1232 AN XY: 54034

African (AFR) AF: 0.0391 AC: 1143 AN: 29252

American (AMR) AF: 0.0107 AC: 114 AN: 10662

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 97 AN: 3080

East Asian (EAS) AF: 0.00644 AC: 27 AN: 4194

South Asian (SAS) AF: 0.0440 AC: 153 AN: 3480

European-Finnish (FIN) AF: 0.00852 AC: 32 AN: 3756

Middle Eastern (MID) AF: 0.0238 AC: 5 AN: 210

European-Non Finnish (NFE) AF: 0.0189 AC: 1117 AN: 59234

Other (OTH) AF: 0.0169 AC: 26 AN: 1538

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs36080695; hg19: chr9-74300311;