1-66981795-C-T

Variant names:

• chr1-66981795-C-T
• rs1665942645
• NM_001077700.3:c.1246C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001077700.3(MIER1):​c.1246C>T​(p.Leu416Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIER1 NM_001077700.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

Genes affected

MIER1 (HGNC:29657): (MIER1 transcriptional regulator) This gene encodes a protein that was first identified in Xenopus laevis by its role in a mesoderm induction early response (MIER). The encoded protein functions as a transcriptional regulator. Alternatively spliced transcript variants encode multiple isoforms, some of which lack a C-terminal nuclear localization signal. [provided by RefSeq, May 2013]

SLC35D1 (HGNC:20800): (solute carrier family 35 member D1) Glycosylation of cellular glycoconjugates occurs in the endoplasmic reticulum (ER) and Golgi compartment, and requires transport of nucleotide sugars from the cytosol into the lumen of the ER and Golgi by specific transporters. The protein encoded by this gene resides in the ER, and transports both UDP-glucuronic acid (UDP-GlcA) and UDP-N-acetylgalactosamine (UDP-GalNAc) from the cytoplasm to the ER lumen. It may participate in glucuronidation and/or chondroitin sulfate biosynthesis. Mutations in this gene are associated with Schneckenbecken dysplasia.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42221594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIER1	NM_001077700.3	c.1246C>T	p.Leu416Phe	missense_variant	Exon 13 of 14	ENST00000401041.6	NP_001071168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIER1	ENST00000401041.6	c.1246C>T	p.Leu416Phe	missense_variant	Exon 13 of 14	2	NM_001077700.3	ENSP00000383820.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1246C>T (p.L416F) alteration is located in exon 13 (coding exon 13) of the MIER1 gene. This alteration results from a C to T substitution at nucleotide position 1246, causing the leucine (L) at amino acid position 416 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	.;.;.;.;.;.;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.2	.;.;.;.;.;.;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.20	N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.32	T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T
Vest4		0.70
MVP		0.31
MPC		0.38
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.13
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1665942645; hg19: chr1-67447478;