1-75136698-G-A

Variant names:

• chr1-75136698-G-A
• rs746324852
• NM_001256114.2:c.75+9G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001256114.2(LHX8):​c.75+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,542,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: LHX8 NM_001256114.2 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.08

Genes affected

LHX8 (HGNC:28838): (LIM homeobox 8) The protein encoded by this gene is a member of the LIM homeobox family of proteins, which are involved in patterning and differentiation of various tissue types. These proteins contain two tandemly repeated cysteine-rich double-zinc finger motifs known as LIM domains, in addition to a DNA-binding homeodomain. This family member is a transcription factor that plays a role in tooth morphogenesis. It is also involved in oogenesis and in neuronal differentiation. This gene is a candidate gene for cleft palate, and it is also associated with odontoma formation. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-75136698-G-A is Benign according to our data. Variant chr1-75136698-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041330.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX8	NM_001256114.2	c.75+9G>A		intron_variant	Intron 2 of 8	ENST00000356261.4	NP_001243043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX8	ENST00000356261.4	c.75+9G>A		intron_variant	Intron 2 of 8	1	NM_001256114.2	ENSP00000348597.3
LHX8	ENST00000294638.9	c.105+9G>A		intron_variant	Intron 3 of 9	1		ENSP00000294638.5
LHX8	ENST00000696555.1	c.168+9G>A		intron_variant	Intron 2 of 8			ENSP00000512714.1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000372 AC: 55 AN: 147666 AF XY: 0.000433

Gnomad AFR exome AF: 0.000122

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000309

Gnomad NFE exome AF: 0.000839

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000598 AC: 831 AN: 1390228 Hom.: 1 Cov.: 30 AF XY: 0.000570 AC XY: 391 AN XY: 686032

African (AFR) AF: 0.0000317 AC: 1 AN: 31530

American (AMR) AF: 0.0000280 AC: 1 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35716

South Asian (SAS) AF: 0.0000632 AC: 5 AN: 79158

European-Finnish (FIN) AF: 0.000308 AC: 13 AN: 42258

Middle Eastern (MID) AF: 0.000197 AC: 1 AN: 5080

European-Non Finnish (NFE) AF: 0.000737 AC: 794 AN: 1077834

Other (OTH) AF: 0.000277 AC: 16 AN: 57826

GnomAD4 genome AF: 0.000362 AC: 55 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74246

African (AFR) AF: 0.000145 AC: 6 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000645 Hom.: 0

Bravo AF: 0.000351

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

LHX8-related disorder Benign:1

May 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		2.1
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

Publications

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Other links and lift over

dbSNP: rs746324852; hg19: chr1-75602383;