chr1-180248001-G-A

Variant names:

• chr1-180248001-G-A
• rs57664116
• NM_033343.4:c.77-284G>A

Variant summary

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

The NM_033343.4(LHX4):​c.77-284G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,138 control chromosomes in the GnomAD database, including 2,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.18 (2691 hom., cov: 33)
• Consequence: LHX4 NM_033343.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0150
• Publications: 0 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]

LHX4 Gene-Disease associations (from GenCC):

• short stature-pituitary and cerebellar defects-small sella turcica syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary stalk interruption syndrome

  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=-0.83).
• BP6: Variant 1-180248001-G-A is Benign according to our data. Variant chr1-180248001-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	NM_033343.4	MANE Select	c.77-284G>A		intron	N/A	NP_203129.1	A0A0S2Z5S4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.77-284G>A		intron	N/A	ENSP00000263726.2	Q969G2
	LHX4	ENST00000930099.1		c.62-284G>A		intron	N/A	ENSP00000600158.1
	LHX4	ENST00000558139.1	TSL:3	n.309-284G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27855 AN: 152020 Hom.: 2690 Cov.: 33

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.0821

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.160

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

GnomAD4 genome AF: 0.183 AC: 27881 AN: 152138 Hom.: 2691 Cov.: 33 AF XY: 0.180 AC XY: 13353 AN XY: 74372

African (AFR) AF: 0.202 AC: 8383 AN: 41486

American (AMR) AF: 0.134 AC: 2050 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3470

East Asian (EAS) AF: 0.158 AC: 818 AN: 5178

South Asian (SAS) AF: 0.0823 AC: 397 AN: 4822

European-Finnish (FIN) AF: 0.181 AC: 1916 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13364 AN: 67982

Other (OTH) AF: 0.159 AC: 335 AN: 2112

Alfa AF: 0.179 Hom.: 335

Bravo AF: 0.181

Asia WGS AF: 0.113 AC: 390 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.0
DANN	Benign	0.64
PhyloP100		0.015
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs57664116; hg19: chr1-180217136;