chr9-71685395-TAA-T

Variant names:

• chr9-71685395-TAA-T
• rs36080695
• NM_013390.3:c.3956-4_3956-3delTT

Variant summary

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

The NM_013390.3(CEMIP2):​c.3956-4_3956-3delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,172,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000052 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0032 (0 hom.)
• Consequence: CEMIP2 NM_013390.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.00949) population. However there is too low homozygotes in high coverage region: (expected more than 2, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEMIP2	NM_013390.3	c.3956-4_3956-3delTT		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.3956-4_3956-3delTT		splice_region_variant, intron_variant	Intron 23 of 23	1	NM_013390.3	ENSP00000366243.4

Frequencies

GnomAD3 genomes AF: 0.0000516 AC: 6 AN: 116350 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000938

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000266

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000675

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00323 AC: 3407 AN: 1056426 Hom.: 0 AF XY: 0.00331 AC XY: 1673 AN XY: 504970

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

African (AFR) AF: 0.000585 AC: 13 AN: 22212

American (AMR) AF: 0.00656 AC: 75 AN: 11430

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 86 AN: 14886

East Asian (EAS) AF: 0.000690 AC: 18 AN: 26092

South Asian (SAS) AF: 0.0104 AC: 323 AN: 30966

European-Finnish (FIN) AF: 0.00488 AC: 117 AN: 23958

Middle Eastern (MID) AF: 0.00341 AC: 10 AN: 2932

European-Non Finnish (NFE) AF: 0.00296 AC: 2604 AN: 881038

Other (OTH) AF: 0.00375 AC: 161 AN: 42912

⚠️ 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: 0.0000516 AC: 6 AN: 116350 Hom.: 0 Cov.: 0 AF XY: 0.0000740 AC XY: 4 AN XY: 54082

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

African (AFR) AF: 0.00 AC: 0 AN: 29244

American (AMR) AF: 0.0000938 AC: 1 AN: 10662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3084

East Asian (EAS) AF: 0.00 AC: 0 AN: 4212

South Asian (SAS) AF: 0.00 AC: 0 AN: 3512

European-Finnish (FIN) AF: 0.000266 AC: 1 AN: 3756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.0000675 AC: 4 AN: 59296

Other (OTH) AF: 0.00 AC: 0 AN: 1534

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0375299), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=97/3	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: rs36080695; hg19: chr9-74300311;