12-56450516-GAA-G

Variant names:

• chr12-56450516-GAA-G
• rs3840772
• ENST00000648304.1:n.*1178_*1179delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000648304.1(ENSG00000285528):​n.*1178_*1179delTT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 152,276 control chromosomes in the GnomAD database, including 38 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000285528 ENST00000648304.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22
• Publications: 1 publications found

Genes affected

ENSG00000285528 (HGNC:):

MIP (HGNC:7103): (major intrinsic protein of lens fiber) Major intrinsic protein is a member of the water-transporting aquaporins as well as the original member of the MIP family of channel proteins. The function of the fiber cell membrane protein encoded by this gene is undetermined, yet this protein is speculated to play a role in intracellular communication. The MIP protein is expressed in the ocular lens and is required for correct lens function. This gene has been mapped among aquaporins AQP2, AQP5, and AQP6, in a potential gene cluster at 12q13. [provided by RefSeq, Jul 2008]

MIP Gene-Disease associations (from GenCC):

• cataract 15 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cerulean cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset sutural cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.01 (1524/152276) while in subpopulation AMR AF = 0.0521 (797/15288). AF 95% confidence interval is 0.0491. There are 38 homozygotes in GnomAd4. There are 844 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIP	NM_012064.4	c.*762_*763delTT		3_prime_UTR_variant	Exon 4 of 4	ENST00000652304.1	NP_036196.1
MIP	XM_011538354.2	c.*762_*763delTT		3_prime_UTR_variant	Exon 6 of 6		XP_011536656.1
MIP	XM_017019306.2	c.*762_*763delTT		3_prime_UTR_variant	Exon 4 of 4		XP_016874795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000285528	ENST00000648304.1	n.*1178_*1179delTT		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000497190.1
MIP	ENST00000652304.1	c.*762_*763delTT		3_prime_UTR_variant	Exon 4 of 4		NM_012064.4	ENSP00000498622.1
ENSG00000285528	ENST00000648304.1	n.*1178_*1179delTT		3_prime_UTR_variant	Exon 4 of 4			ENSP00000497190.1

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1515 AN: 152158 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 72 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0100 AC: 1524 AN: 152276 Hom.: 38 Cov.: 32 AF XY: 0.0113 AC XY: 844 AN XY: 74456

African (AFR) AF: 0.00190 AC: 79 AN: 41560

American (AMR) AF: 0.0521 AC: 797 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.0338 AC: 175 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0340 AC: 360 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68032

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00540 Hom.: 6

Bravo AF: 0.0129

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
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: rs3840772; hg19: chr12-56844300;