chr1-180272020-G-T

Position:

• chr1-180272020-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACBD6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 262224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-180272020-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX4	NM_033343.4	c.778+14G>T		intron_variant		ENST00000263726.4	NP_203129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.778+14G>T		intron_variant		1	NM_033343.4	ENSP00000263726.2
ACBD6	ENST00000642319.1	c.*1254-49C>A		intron_variant				ENSP00000495710.1
ACBD6	ENST00000415414.5	n.349-49C>A		intron_variant		2
ACBD6	ENST00000645415.1	n.*1487-49C>A		intron_variant				ENSP00000494507.1

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

GnomAD3 exomes AF: 0.104 AC: 25553 AN: 246848 Hom.: 2449 AF XY: 0.0936 AC XY: 12483 AN XY: 133332

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 SAS exome AF: 0.0584

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

Gnomad4 AFR exome AF: 0.0942

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.0522

Gnomad4 SAS exome AF: 0.0594

Gnomad4 FIN exome AF: 0.0673

Gnomad4 NFE exome AF: 0.0835

Gnomad4 OTH exome AF: 0.0748

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

Gnomad4 AFR AF: 0.0950

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.0434

Gnomad4 SAS AF: 0.0553

Gnomad4 FIN AF: 0.0690

Gnomad4 NFE AF: 0.0823

Gnomad4 OTH AF: 0.0711

Alfa AF: 0.0716 Hom.: 459

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs3806302; hg19: chr1-180241155;