12-122274172-TAA-TAAAA

Variant names:

• chr12-122274172-T-TAA
• rs376224001
• NM_001247997.2:c.3967-12_3967-11dupTT

Variant summary

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

The NM_001247997.2(CLIP1):​c.3967-12_3967-11dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,277,230 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CLIP1 NM_001247997.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.14
• Publications: 0 publications found

Genes affected

CLIP1 (HGNC:10461): (CAP-Gly domain containing linker protein 1) The protein encoded by this gene links endocytic vesicles to microtubules. This gene is highly expressed in Reed-Sternberg cells of Hodgkin disease. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

CLIP1 Gene-Disease associations (from GenCC):

• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001247997.2. 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
	CLIP1	NM_001247997.2	MANE Select	c.3967-12_3967-11dupTT		intron	N/A	NP_001234926.1	P30622-3
	CLIP1	NM_001389291.1		c.6097-12_6097-11dupTT		intron	N/A	NP_001376220.1
	CLIP1	NM_002956.3		c.3934-12_3934-11dupTT		intron	N/A	NP_002947.1	P30622-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP1	ENST00000620786.5	TSL:5 MANE Select	c.3967-12_3967-11dupTT		intron	N/A	ENSP00000479322.1	P30622-3
	CLIP1	ENST00000358808.6	TSL:1	c.3934-12_3934-11dupTT		intron	N/A	ENSP00000351665.2	P30622-1
	CLIP1	ENST00000537178.5	TSL:1	c.3829-12_3829-11dupTT		intron	N/A	ENSP00000445531.1	P30622-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 7 AN: 1277230 Hom.: 0 Cov.: 24 AF XY: 0.00000315 AC XY: 2 AN XY: 635534

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

African (AFR) AF: 0.0000345 AC: 1 AN: 28978

American (AMR) AF: 0.00 AC: 0 AN: 37794

Ashkenazi Jewish (ASJ) AF: 0.0000451 AC: 1 AN: 22156

East Asian (EAS) AF: 0.00 AC: 0 AN: 34038

South Asian (SAS) AF: 0.00 AC: 0 AN: 73652

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5172

European-Non Finnish (NFE) AF: 0.00000410 AC: 4 AN: 976632

Other (OTH) AF: 0.00 AC: 0 AN: 52298

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.1
BranchPoint Hunter		4.0

Splicing

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

Other links and lift over

dbSNP: rs376224001; hg19: chr12-122758719;