rs7860634

Variant names:

• chr9-136197833-G-A
• rs7860634
• NM_178138.6:c.776-90C>T

Variant summary

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

The NM_178138.6(LHX3):​c.776-90C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,422,906 control chromosomes in the GnomAD database, including 216,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23154 hom., cov: 33)
  • Exomes 𝑓: 0.55 (193493 hom.)
• Consequence: LHX3 NM_178138.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.721
• Publications: 24 publications found

Genes affected

LHX3 (HGNC:6595): (LIM homeobox 3) This gene encodes a member of a large family of proteins which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Mutations in this gene cause combined pituitary hormone deficiency 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

LHX3 Gene-Disease associations (from GenCC):

• non-acquired combined pituitary hormone deficiency with spine abnormalities

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-136197833-G-A is Benign according to our data. Variant chr9-136197833-G-A is described in ClinVar as Benign. ClinVar VariationId is 1185281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178138.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	NM_178138.6	MANE Select	c.776-90C>T		intron	N/A	NP_835258.1
	LHX3	NM_014564.5		c.791-90C>T		intron	N/A	NP_055379.1
	LHX3	NM_001363746.1		c.743-90C>T		intron	N/A	NP_001350675.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX3	ENST00000371748.10	TSL:1 MANE Select	c.776-90C>T		intron	N/A	ENSP00000360813.4
	LHX3	ENST00000371746.9	TSL:1	c.791-90C>T		intron	N/A	ENSP00000360811.3
	LHX3	ENST00000619587.1	TSL:1	c.743-90C>T		intron	N/A	ENSP00000483080.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83266 AN: 151960 Hom.: 23135 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.549

GnomAD4 exome AF: 0.549 AC: 697469 AN: 1270828 Hom.: 193493 AF XY: 0.546 AC XY: 347628 AN XY: 636214

African (AFR) AF: 0.582 AC: 17303 AN: 29738

American (AMR) AF: 0.395 AC: 15225 AN: 38582

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 12119 AN: 24576

East Asian (EAS) AF: 0.356 AC: 13035 AN: 36658

South Asian (SAS) AF: 0.454 AC: 35508 AN: 78140

European-Finnish (FIN) AF: 0.553 AC: 19339 AN: 34978

Middle Eastern (MID) AF: 0.556 AC: 2836 AN: 5102

European-Non Finnish (NFE) AF: 0.571 AC: 553008 AN: 968754

Other (OTH) AF: 0.536 AC: 29096 AN: 54300

GnomAD4 genome AF: 0.548 AC: 83320 AN: 152078 Hom.: 23154 Cov.: 33 AF XY: 0.543 AC XY: 40352 AN XY: 74332

African (AFR) AF: 0.582 AC: 24125 AN: 41482

American (AMR) AF: 0.475 AC: 7260 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3472

East Asian (EAS) AF: 0.348 AC: 1789 AN: 5148

South Asian (SAS) AF: 0.445 AC: 2146 AN: 4818

European-Finnish (FIN) AF: 0.551 AC: 5831 AN: 10580

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38561 AN: 67958

Other (OTH) AF: 0.546 AC: 1155 AN: 2114

Alfa AF: 0.546 Hom.: 32327

Bravo AF: 0.543

Asia WGS AF: 0.423 AC: 1470 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Non-acquired combined pituitary hormone deficiency with spine abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.35
DANN	Benign	0.32
PhyloP100		-0.72
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: rs7860634; hg19: chr9-139089679;