NM_033343.4:c.450C>T

Variant names:

• chr1-180266593-C-T
• rs16855642
• NM_033343.4:c.450C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033343.4(LHX4):​c.450C>T​(p.Asn150Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,830 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (265 hom., cov: 32)
  • Exomes 𝑓: 0.014 (286 hom.)
• Consequence: LHX4 NM_033343.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004384
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.769
• Publications: 12 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-180266593-C-T is Benign according to our data. Variant chr1-180266593-C-T is described in ClinVar as Benign. ClinVar VariationId is 262223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.769 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.450C>T	p.Asn150Asn	splice_region synonymous	Exon 3 of 6	NP_203129.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.450C>T	p.Asn150Asn	splice_region synonymous	Exon 3 of 6	ENSP00000263726.2
	LHX4	ENST00000561113.1	TSL:2	n.386C>T		splice_region non_coding_transcript_exon	Exon 2 of 4	ENSP00000452783.1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5918 AN: 152112 Hom.: 261 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0190 AC: 4763 AN: 250414 AF XY: 0.0173

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00918

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0271

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0139 AC: 20282 AN: 1461602 Hom.: 286 Cov.: 32 AF XY: 0.0136 AC XY: 9878 AN XY: 727088

African (AFR) AF: 0.101 AC: 3378 AN: 33472

American (AMR) AF: 0.0102 AC: 455 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 392 AN: 26130

East Asian (EAS) AF: 0.0193 AC: 767 AN: 39688

South Asian (SAS) AF: 0.0172 AC: 1487 AN: 86222

European-Finnish (FIN) AF: 0.0243 AC: 1298 AN: 53400

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5768

European-Non Finnish (NFE) AF: 0.0101 AC: 11282 AN: 1111822

Other (OTH) AF: 0.0182 AC: 1102 AN: 60384

GnomAD4 genome AF: 0.0391 AC: 5946 AN: 152228 Hom.: 265 Cov.: 32 AF XY: 0.0382 AC XY: 2844 AN XY: 74438

African (AFR) AF: 0.104 AC: 4298 AN: 41508

American (AMR) AF: 0.0182 AC: 279 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3472

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5178

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4826

European-Finnish (FIN) AF: 0.0272 AC: 289 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 762 AN: 68000

Other (OTH) AF: 0.0364 AC: 77 AN: 2114

Alfa AF: 0.0193 Hom.: 312

Bravo AF: 0.0402

Asia WGS AF: 0.0350 AC: 123 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0112

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	-0.53
CADD	Benign	9.0
DANN	Benign	0.88
PhyloP100		-0.77
Mutation Taster		=74/26	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.054
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: rs16855642; hg19: chr1-180235728; COSMIC: COSV107227508; COSMIC: COSV107227508;