NM_001247997.2:c.7A>G

Variant names:

• chr12-122380446-T-C
• rs140092191
• NM_001247997.2:c.7A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001247997.2(CLIP1):​c.7A>G​(p.Met3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,610,882 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: CLIP1 NM_001247997.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011199325).
• BS2: High Homozygotes in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP1	NM_001247997.2	MANE Select	c.7A>G	p.Met3Val	missense	Exon 2 of 26	NP_001234926.1
	CLIP1	NM_001389291.1		c.7A>G	p.Met3Val	missense	Exon 2 of 25	NP_001376220.1
	CLIP1	NM_002956.3		c.7A>G	p.Met3Val	missense	Exon 2 of 25	NP_002947.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIP1	ENST00000620786.5	TSL:5 MANE Select	c.7A>G	p.Met3Val	missense	Exon 2 of 26	ENSP00000479322.1
	CLIP1	ENST00000358808.6	TSL:1	c.7A>G	p.Met3Val	missense	Exon 2 of 25	ENSP00000351665.2
	CLIP1	ENST00000537178.5	TSL:1	c.7A>G	p.Met3Val	missense	Exon 2 of 24	ENSP00000445531.1

Frequencies

GnomAD3 genomes AF: 0.000972 AC: 148 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000808 AC: 201 AN: 248842 AF XY: 0.000854

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000964

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00111 AC: 1626 AN: 1458560 Hom.: 5 Cov.: 29 AF XY: 0.00111 AC XY: 805 AN XY: 725806

African (AFR) AF: 0.0000901 AC: 3 AN: 33294

American (AMR) AF: 0.00221 AC: 98 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85950

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53324

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00130 AC: 1447 AN: 1109944

Other (OTH) AF: 0.00113 AC: 68 AN: 60260

GnomAD4 genome AF: 0.000972 AC: 148 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74486

African (AFR) AF: 0.000313 AC: 13 AN: 41572

American (AMR) AF: 0.00275 AC: 42 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000960

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000576 AC: 70

EpiCase AF: 0.00121

EpiControl AF: 0.00125

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	8.0
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Uncertain	0.025	D
Sift4G	Benign	0.40	T
Polyphen		0.023	B
Vest4		0.22
MVP		0.78
MPC		0.42
ClinPred		0.022	T
GERP RS		1.3
PromoterAI		0.0085	Neutral
Varity_R		0.16
gMVP		0.41
Mutation Taster		=100/0	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: rs140092191; hg19: chr12-122864993;