1-180271831-GCAGGTTTGGTTT-G

Position:

• chr1-180271831-GCAGGTTTGGTTT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_033343.4(LHX4):​c.607_618delGTTTGGTTTCAG​(p.Val203_Gln206del) variant causes a conservative inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LHX4 NM_033343.4 conservative_inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity LHX4_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_033343.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_033343.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX4	NM_033343.4	c.607_618delGTTTGGTTTCAG	p.Val203_Gln206del	conservative_inframe_deletion, splice_region_variant	5/6	ENST00000263726.4	NP_203129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.607_618delGTTTGGTTTCAG	p.Val203_Gln206del	conservative_inframe_deletion, splice_region_variant	5/6	1	NM_033343.4	ENSP00000263726.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 4 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-180240966;