NM_182548.4:c.411G>C

Variant names:

• chr6-35806081-G-C
• rs140326236
• NM_182548.4:c.411G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_182548.4(LHFPL5):​c.411G>C​(p.Ala137Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A137A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LHFPL5 NM_182548.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00004754
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.65
• Publications: 1 publications found

Genes affected

LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) 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 this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]

LHFPL5 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 67

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-6.65 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182548.4. 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
	LHFPL5	NM_182548.4	MANE Select	c.411G>C	p.Ala137Ala	splice_region synonymous	Exon 1 of 4	NP_872354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHFPL5	ENST00000360215.3	TSL:1 MANE Select	c.411G>C	p.Ala137Ala	splice_region synonymous	Exon 1 of 4	ENSP00000353346.1
	LHFPL5	ENST00000651132.1		c.411G>C	p.Ala137Ala	splice_region synonymous	Exon 4 of 7	ENSP00000498322.1
	LHFPL5	ENST00000651676.1		c.411G>C	p.Ala137Ala	splice_region synonymous	Exon 1 of 4	ENSP00000498699.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.015
DANN	Benign	0.52
PhyloP100		-6.6
PromoterAI		0.0096	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.078
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: rs140326236; hg19: chr6-35773858;