Genetic Variant DIAPH1:p.Leu1059Val (chr5-141527669-TAG-GAC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_005219.5(DIAPH1):c.3175_3177delCTAinsGTC (p.Leu1059Val) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.24). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L1059V: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 578663) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 28)

Consequence

DIAPH1
NM_005219.5 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.25

Publications

0 publications found

Variant links:

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

DIAPH1 links:

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new If you want to explore the variant's impact on the transcript NM_005219.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
DIAPH1 NM_005219.5	MANE Select	c.3175_3177delCTAinsGTC p.Leu1059Val	missense	N/A	Prot: NP_005210.3
DIAPH1 NM_001079812.3		c.3148_3150delCTAinsGTC p.Leu1050Val	missense	N/A	Prot: NP_001073280.1 UniProt: O60610-3
DIAPH1 NM_001314007.2		c.3175_3177delCTAinsGTC p.Leu1059Val	missense	N/A	Prot: NP_001300936.1 UniProt: A0A2R8Y5N1

DIAPH1 NM_005219.5

MANE Select

HGVSc / HGVSpc.3175_3177delCTAinsGTCp.Leu1059Val

Exon rankN/A

missense

Prot: NP_005210.3

DIAPH1 NM_001079812.3

HGVSc / HGVSpc.3148_3150delCTAinsGTCp.Leu1050Val

Exon rankN/A

missense

Prot: NP_001073280.1UniProt: O60610-3

DIAPH1 NM_001314007.2

HGVSc / HGVSpc.3175_3177delCTAinsGTCp.Leu1059Val

Exon rankN/A

missense

Prot: NP_001300936.1UniProt: A0A2R8Y5N1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
DIAPH1 ENST00000389054.8	TSL:5MANE Select	c.3175_3177delCTAinsGTC p.Leu1059Val	missense	N/A	Prot: ENSP00000373706.4 UniProt: O60610-1
DIAPH1 ENST00000518047.5	TSL:5	c.3148_3150delCTAinsGTC p.Leu1050Val	missense	N/A	Prot: ENSP00000428268.2 UniProt: O60610-3
DIAPH1 ENST00000647433.1		c.3175_3177delCTAinsGTC p.Leu1059Val	missense	N/A	Prot: ENSP00000494675.1 UniProt: A0A2R8Y5N1

DIAPH1 ENST00000389054.8

TSL:5MANE Select

HGVSc / HGVSpc.3175_3177delCTAinsGTCp.Leu1059Val

Exon rankN/A

missense

Prot: ENSP00000373706.4UniProt: O60610-1

DIAPH1 ENST00000518047.5

TSL:5

HGVSc / HGVSpc.3148_3150delCTAinsGTCp.Leu1050Val

Exon rankN/A

missense

Prot: ENSP00000428268.2UniProt: O60610-3

DIAPH1 ENST00000647433.1

HGVSc / HGVSpc.3175_3177delCTAinsGTCp.Leu1059Val

Exon rankN/A

missense

Prot: ENSP00000494675.1UniProt: A0A2R8Y5N1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:28
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:28

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence