NM_177398.4:c.818-103C>T

Variant names:

• chr1-165206137-G-A
• rs4656435
• NM_177398.4:c.818-103C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177398.4(LMX1A):​c.818-103C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.62 in 1,100,484 control chromosomes in the GnomAD database, including 216,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25688 hom., cov: 32)
  • Exomes 𝑓: 0.63 (191159 hom.)
• Consequence: LMX1A NM_177398.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.87
• Publications: 8 publications found

Genes affected

LMX1A (HGNC:6653): (LIM homeobox transcription factor 1 alpha) This gene encodes a homeodomain and LIM-domain containing protein. The encoded protein is a transcription factor that acts as a positive regulator of insulin gene transcription. This gene also plays a role in the development of dopamine producing neurons during embryogenesis. Mutations in this gene are associated with an increased risk of developing Parkinson's disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

LMX1A-AS2 (HGNC:40343): (LMX1A antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-165206137-G-A is Benign according to our data. Variant chr1-165206137-G-A is described in ClinVar as [Benign]. Clinvar id is 1294822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMX1A	NM_177398.4	c.818-103C>T		intron_variant	Intron 7 of 8	ENST00000342310.7	NP_796372.1
LMX1A	NM_001174069.2	c.818-103C>T		intron_variant	Intron 7 of 8		NP_001167540.1
LMX1A	XM_011509538.4	c.578-103C>T		intron_variant	Intron 5 of 6		XP_011507840.1
LMX1A-AS2	XR_922234.2	n.366+367G>A		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMX1A	ENST00000342310.7	c.818-103C>T		intron_variant	Intron 7 of 8	2	NM_177398.4	ENSP00000340226.3
LMX1A	ENST00000367893.4	c.818-103C>T		intron_variant	Intron 6 of 7	1		ENSP00000356868.4
LMX1A	ENST00000489443.2	n.452-103C>T		intron_variant	Intron 5 of 6	1
LMX1A	ENST00000294816.6	c.818-103C>T		intron_variant	Intron 7 of 8	2		ENSP00000294816.2

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86939 AN: 151914 Hom.: 25672 Cov.: 32

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.628 AC: 595454 AN: 948452 Hom.: 191159 AF XY: 0.624 AC XY: 296662 AN XY: 475456

African (AFR) AF: 0.471 AC: 9792 AN: 20810

American (AMR) AF: 0.409 AC: 9234 AN: 22578

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 9280 AN: 16586

East Asian (EAS) AF: 0.298 AC: 9914 AN: 33324

South Asian (SAS) AF: 0.463 AC: 25336 AN: 54708

European-Finnish (FIN) AF: 0.665 AC: 31617 AN: 47526

Middle Eastern (MID) AF: 0.590 AC: 1932 AN: 3274

European-Non Finnish (NFE) AF: 0.668 AC: 472939 AN: 707930

Other (OTH) AF: 0.609 AC: 25410 AN: 41716

GnomAD4 genome AF: 0.572 AC: 86997 AN: 152032 Hom.: 25688 Cov.: 32 AF XY: 0.566 AC XY: 42039 AN XY: 74320

African (AFR) AF: 0.477 AC: 19746 AN: 41438

American (AMR) AF: 0.508 AC: 7769 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1887 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1442 AN: 5158

South Asian (SAS) AF: 0.441 AC: 2128 AN: 4826

European-Finnish (FIN) AF: 0.657 AC: 6952 AN: 10578

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 44966 AN: 67968

Other (OTH) AF: 0.587 AC: 1237 AN: 2108

Alfa AF: 0.629 Hom.: 18006

Bravo AF: 0.557

Asia WGS AF: 0.354 AC: 1229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs4656435; hg19: chr1-165175374;