12-122274172-TAA-TA

Variant names:

• chr12-122274172-TA-T
• rs376224001
• NM_001247997.2:c.3967-11delT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001247997.2(CLIP1):​c.3967-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,360,464 control chromosomes in the GnomAD database, including 19 homozygotes. 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: 𝑓 0.00086 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (17 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.3967-11delT		intron	N/A	NP_001234926.1	P30622-3
	CLIP1	NM_001389291.1		c.6097-11delT		intron	N/A	NP_001376220.1
	CLIP1	NM_002956.3		c.3934-11delT		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.3967-11delT		intron	N/A	ENSP00000479322.1	P30622-3
	CLIP1	ENST00000358808.6	TSL:1	c.3934-11delT		intron	N/A	ENSP00000351665.2	P30622-1
	CLIP1	ENST00000537178.5	TSL:1	c.3829-11delT		intron	N/A	ENSP00000445531.1	P30622-2

Frequencies

GnomAD3 genomes AF: 0.000856 AC: 128 AN: 149558 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.000100

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00944 AC: 1464 AN: 155128 AF XY: 0.0103

Gnomad AFR exome AF: 0.00306

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00503

Gnomad FIN exome AF: 0.00672

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00892 AC: 10795 AN: 1210808 Hom.: 17 Cov.: 24 AF XY: 0.00904 AC XY: 5432 AN XY: 601076

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

African (AFR) AF: 0.00922 AC: 253 AN: 27428

American (AMR) AF: 0.00858 AC: 300 AN: 34956

Ashkenazi Jewish (ASJ) AF: 0.00933 AC: 191 AN: 20482

East Asian (EAS) AF: 0.00912 AC: 287 AN: 31464

South Asian (SAS) AF: 0.0223 AC: 1508 AN: 67532

European-Finnish (FIN) AF: 0.00804 AC: 351 AN: 43656

Middle Eastern (MID) AF: 0.00666 AC: 33 AN: 4956

European-Non Finnish (NFE) AF: 0.00793 AC: 7382 AN: 930938

Other (OTH) AF: 0.00992 AC: 490 AN: 49396

⚠️ 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: 0.000862 AC: 129 AN: 149656 Hom.: 2 Cov.: 32 AF XY: 0.00100 AC XY: 73 AN XY: 73036

African (AFR) AF: 0.00134 AC: 55 AN: 40936

American (AMR) AF: 0.000200 AC: 3 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.0120 AC: 57 AN: 4754

European-Finnish (FIN) AF: 0.000100 AC: 1 AN: 9996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000179 AC: 12 AN: 67168

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.0332 Hom.: 0

Bravo AF: 0.000604

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.1
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs376224001; hg19: chr12-122758719; COSMIC: COSV56801095; COSMIC: COSV56801095;