rs989798

Variant names:

• chr9-122209763-C-T
• rs989798
• NM_014368.5:c.1055-46G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014368.5(LHX6):​c.1055-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 745,424 control chromosomes in the GnomAD database, including 33,098 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (6065 hom., cov: 32)
  • Exomes 𝑓: 0.29 (27033 hom.)
• Consequence: LHX6 NM_014368.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0330
• Publications: 8 publications found

Genes affected

LHX6 (HGNC:21735): (LIM homeobox 6) This gene encodes a member of a large protein family that contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein has tandem LIM domains as well as a DNA-binding homeodomain. The protein functions as a transcription factor involved in embryogenesis and head development and is highly expressed in neural crest derived mesenchyme cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

LHX6 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX6	NM_014368.5	MANE Select	c.1055-46G>A		intron	N/A	NP_055183.2	Q9UPM6-3
	LHX6	NM_199160.4		c.1054+3843G>A		intron	N/A	NP_954629.2	Q9UPM6-4
	LHX6	NM_001242333.2		c.1021+3843G>A		intron	N/A	NP_001229262.1	Q9UPM6-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX6	ENST00000394319.9	TSL:1 MANE Select	c.1055-46G>A		intron	N/A	ENSP00000377854.4	Q9UPM6-3
	LHX6	ENST00000340587.7	TSL:1	c.1054+3843G>A		intron	N/A	ENSP00000340137.3	Q9UPM6-4
	LHX6	ENST00000373755.6	TSL:1	c.968-46G>A		intron	N/A	ENSP00000362860.2	Q9UPM6-1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41680 AN: 151970 Hom.: 6065 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.283 AC: 57747 AN: 203740 AF XY: 0.282

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.293 AC: 173703 AN: 593336 Hom.: 27033 Cov.: 5 AF XY: 0.287 AC XY: 91969 AN XY: 320746

African (AFR) AF: 0.196 AC: 3403 AN: 17336

American (AMR) AF: 0.209 AC: 8565 AN: 41020

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 6325 AN: 18448

East Asian (EAS) AF: 0.253 AC: 8991 AN: 35474

South Asian (SAS) AF: 0.133 AC: 8333 AN: 62592

European-Finnish (FIN) AF: 0.356 AC: 16992 AN: 47762

Middle Eastern (MID) AF: 0.358 AC: 1411 AN: 3944

European-Non Finnish (NFE) AF: 0.328 AC: 110001 AN: 335090

Other (OTH) AF: 0.306 AC: 9682 AN: 31670

GnomAD4 genome AF: 0.274 AC: 41674 AN: 152088 Hom.: 6065 Cov.: 32 AF XY: 0.270 AC XY: 20034 AN XY: 74320

African (AFR) AF: 0.196 AC: 8139 AN: 41518

American (AMR) AF: 0.231 AC: 3528 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3468

East Asian (EAS) AF: 0.299 AC: 1543 AN: 5156

South Asian (SAS) AF: 0.129 AC: 623 AN: 4826

European-Finnish (FIN) AF: 0.345 AC: 3651 AN: 10570

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.327 AC: 22218 AN: 67950

Other (OTH) AF: 0.268 AC: 567 AN: 2114

Alfa AF: 0.310 Hom.: 1671

Bravo AF: 0.266

Asia WGS AF: 0.223 AC: 774 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.74
PhyloP100		-0.033
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs989798; hg19: chr9-124972042;