X-112631592-C-G

Variant names:

• chrX-112631592-C-G
• rs370162233
• NM_178175.4:c.491G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178175.4(LHFPL1):​c.491G>C​(p.Arg164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000926 in 1,079,853 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: LHFPL1 NM_178175.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• Publications: 0 publications found

Genes affected

LHFPL1 (HGNC:6587): (LHFPL tetraspan subfamily member 1) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in one LHFP-like gene result in deafness in humans and mice, and a second LHFP-like gene is fused to a high-mobility group gene in a translocation-associated lipoma. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4210589).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178175.4. 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
	LHFPL1	NM_178175.4	MANE Select	c.491G>C	p.Arg164Pro	missense	Exon 4 of 4	NP_835469.1	Q86WI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHFPL1	ENST00000371968.8	TSL:1 MANE Select	c.491G>C	p.Arg164Pro	missense	Exon 4 of 4	ENSP00000361036.3	Q86WI0-1
	LHFPL1	ENST00000864007.1		c.491G>C	p.Arg164Pro	missense	Exon 4 of 4	ENSP00000534066.1
	LHFPL1	ENST00000864010.1		c.491G>C	p.Arg164Pro	missense	Exon 4 of 4	ENSP00000534070.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.26e-7 AC: 1 AN: 1079853 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 347395

African (AFR) AF: 0.00 AC: 0 AN: 26120

American (AMR) AF: 0.00 AC: 0 AN: 34714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18934

East Asian (EAS) AF: 0.00 AC: 0 AN: 29924

South Asian (SAS) AF: 0.00 AC: 0 AN: 51785

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40203

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3909

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 829010

Other (OTH) AF: 0.00 AC: 0 AN: 45254

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.27	B
Vest4		0.48
MutPred		0.33		Loss of sheet (P = 0.0228)
MVP		0.62
MPC		0.26
ClinPred		0.40	T
GERP RS		-0.89
Varity_R		0.36
gMVP		0.86
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370162233; hg19: chrX-111874820;