rs565557892

Variant names:

• chr1-180230396-G-C
• rs565557892
• NM_033343.4:c.-134G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-180230396-G-C
• chr1-180230396-G-A
• chr1-180230396-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_033343.4(LHX4):​c.-134G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000581 in 756,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: LHX4 NM_033343.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000165 (25/151912) while in subpopulation AFR AF = 0.000555 (23/41434). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 AD gene.

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.-134G>C		5_prime_UTR	Exon 1 of 6	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.-134G>C		5_prime_UTR	Exon 1 of 6	ENSP00000263726.2	Q969G2
	LHX4	ENST00000930099.1		c.-134G>C		5_prime_UTR	Exon 1 of 6	ENSP00000600158.1
	LHX4	ENST00000558139.1	TSL:3	n.99G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.000165 AC: 25 AN: 151800 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000314 AC: 19 AN: 604760 Hom.: 0 Cov.: 8 AF XY: 0.0000310 AC XY: 10 AN XY: 322748

African (AFR) AF: 0.000301 AC: 5 AN: 16606

American (AMR) AF: 0.00 AC: 0 AN: 34144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19760

East Asian (EAS) AF: 0.000125 AC: 4 AN: 32072

South Asian (SAS) AF: 0.00 AC: 0 AN: 62158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2764

European-Non Finnish (NFE) AF: 0.0000216 AC: 8 AN: 371062

Other (OTH) AF: 0.0000626 AC: 2 AN: 31928

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151912 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 16 AN XY: 74236

African (AFR) AF: 0.000555 AC: 23 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000170

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Short stature-pituitary and cerebellar defects-small sella turcica syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		1.1
PromoterAI		-0.012	Neutral

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: rs565557892; hg19: chr1-180199531;