1-180272020-G-T

Variant names:

• chr1-180272020-G-T
• rs3806302
• NM_033343.4:c.778+14G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_033343.4(LHX4):​c.778+14G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,608,636 control chromosomes in the GnomAD database, including 7,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (841 hom., cov: 31)
  • Exomes 𝑓: 0.086 (6844 hom.)
• Consequence: LHX4 NM_033343.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.384
• Publications: 5 publications found

Genes affected

LHX4 (HGNC:21734): (LIM homeobox 4) This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor involved in the control of differentiation and development of the pituitary gland. Mutations in this gene cause combined pituitary hormone deficiency 4. [provided by RefSeq, Dec 2010]

ACBD6 (HGNC:23339): (acyl-CoA binding domain containing 6) Predicted to enable fatty-acyl-CoA binding activity and lipid binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LHX4-AS1 (HGNC:40982): (LHX4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 1-180272020-G-T is Benign according to our data. Variant chr1-180272020-G-T is described in ClinVar as Benign. ClinVar VariationId is 262224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033343.4. 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
	LHX4	NM_033343.4	MANE Select	c.778+14G>T		intron	N/A	NP_203129.1
	LHX4-AS1	NR_037642.1		n.349-49C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.778+14G>T		intron	N/A	ENSP00000263726.2
	ACBD6	ENST00000642319.1		c.*1254-49C>A		intron	N/A	ENSP00000495710.1
	ACBD6	ENST00000415414.5	TSL:2	n.349-49C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0911 AC: 13800 AN: 151562 Hom.: 832 Cov.: 31

Gnomad AFR AF: 0.0950

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.0440

Gnomad SAS AF: 0.0549

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.0718

GnomAD2 exomes AF: 0.104 AC: 25553 AN: 246848 AF XY: 0.0936

Gnomad AFR exome AF: 0.0992

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0368

Gnomad FIN exome AF: 0.0660

Gnomad NFE exome AF: 0.0794

Gnomad OTH exome AF: 0.0881

GnomAD4 exome AF: 0.0857 AC: 124789 AN: 1456954 Hom.: 6844 Cov.: 32 AF XY: 0.0837 AC XY: 60619 AN XY: 724512

African (AFR) AF: 0.0942 AC: 3140 AN: 33348

American (AMR) AF: 0.298 AC: 13210 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 346 AN: 25844

East Asian (EAS) AF: 0.0522 AC: 2070 AN: 39664

South Asian (SAS) AF: 0.0594 AC: 5098 AN: 85872

European-Finnish (FIN) AF: 0.0673 AC: 3559 AN: 52856

Middle Eastern (MID) AF: 0.0342 AC: 171 AN: 4994

European-Non Finnish (NFE) AF: 0.0835 AC: 92698 AN: 1109902

Other (OTH) AF: 0.0748 AC: 4497 AN: 60130

GnomAD4 genome AF: 0.0912 AC: 13827 AN: 151682 Hom.: 841 Cov.: 31 AF XY: 0.0923 AC XY: 6834 AN XY: 74066

African (AFR) AF: 0.0950 AC: 3933 AN: 41384

American (AMR) AF: 0.187 AC: 2852 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.0434 AC: 221 AN: 5098

South Asian (SAS) AF: 0.0553 AC: 260 AN: 4698

European-Finnish (FIN) AF: 0.0690 AC: 727 AN: 10534

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0823 AC: 5590 AN: 67934

Other (OTH) AF: 0.0711 AC: 150 AN: 2110

Alfa AF: 0.0778 Hom.: 723

Bravo AF: 0.103

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Short stature-pituitary and cerebellar defects-small sella turcica syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3806302; hg19: chr1-180241155;