1-180271918-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033343.4(LHX4):c.690C>T(p.Ser230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,613,352 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: LHX4 NM_033343.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42

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-AS1 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-180271918-C-T is Benign according to our data. Variant chr1-180271918-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 720999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-180271918-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00333 (504/151526) while in subpopulation AFR AF= 0.0114 (472/41262). AF 95% confidence interval is 0.0106. There are 2 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 506 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LHX4	NM_033343.4	c.690C>T	p.Ser230=	synonymous_variant	5/6	ENST00000263726.4
LHX4-AS1	NR_037642.1	n.402G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX4	ENST00000263726.4	c.690C>T	p.Ser230=	synonymous_variant	5/6	1	NM_033343.4	P1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 506 AN: 151410 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00102 AC: 257 AN: 251384 Hom.: 2 AF XY: 0.000626 AC XY: 85 AN XY: 135864

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000375 AC: 548 AN: 1461826 Hom.: 3 Cov.: 32 AF XY: 0.000304 AC XY: 221 AN XY: 727220

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00333 AC: 504 AN: 151526 Hom.: 2 Cov.: 31 AF XY: 0.00296 AC XY: 219 AN XY: 73994

Gnomad4 AFR AF: 0.0114

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00411

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 18, 2023

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	7.1
Dann	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs111822893; hg19: chr1-180241053;