Genetic Variant NM_005219.5:c.3175_3177delCTAinsGTT (chr5-141527669-TAG-AAC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_005219.5(DIAPH1):c.3175_3177delCTAinsGTT (p.Leu1059Val) variant causes a missense change. The gene DIAPH1 is a known oncogene (CancerMine: 1 oncogene, 1 driver citations). The gene DIAPH1 is a cancer driver gene (CancerMine: 1 oncogene, 1 driver citations). 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 ACGS-UK Somatic Oncogenicity v2025

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
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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_3177delCTAinsGTT p.Leu1059Val	missense	N/A	Prot: NP_005210.3
DIAPH1 NM_001079812.3		c.3148_3150delCTAinsGTT p.Leu1050Val	missense	N/A	Prot: NP_001073280.1 UniProt: O60610-3
DIAPH1 NM_001314007.2		c.3175_3177delCTAinsGTT p.Leu1059Val	missense	N/A	Prot: NP_001300936.1 UniProt: A0A2R8Y5N1

DIAPH1 NM_005219.5

MANE Select

HGVSc / HGVSpc.3175_3177delCTAinsGTTp.Leu1059Val

Exon rankN/A

missense

Prot: NP_005210.3

DIAPH1 NM_001079812.3

HGVSc / HGVSpc.3148_3150delCTAinsGTTp.Leu1050Val

Exon rankN/A

missense

Prot: NP_001073280.1UniProt: O60610-3

DIAPH1 NM_001314007.2

HGVSc / HGVSpc.3175_3177delCTAinsGTTp.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_3177delCTAinsGTT p.Leu1059Val	missense	N/A	Prot: ENSP00000373706.4 UniProt: O60610-1
DIAPH1 ENST00000518047.5	TSL:5	c.3148_3150delCTAinsGTT p.Leu1050Val	missense	N/A	Prot: ENSP00000428268.2 UniProt: O60610-3
DIAPH1 ENST00000647433.1		c.3175_3177delCTAinsGTT p.Leu1059Val	missense	N/A	Prot: ENSP00000494675.1 UniProt: A0A2R8Y5N1

DIAPH1 ENST00000389054.8

TSL:5MANE Select

HGVSc / HGVSpc.3175_3177delCTAinsGTTp.Leu1059Val

Exon rankN/A

missense

Prot: ENSP00000373706.4UniProt: O60610-1

DIAPH1 ENST00000518047.5

TSL:5

HGVSc / HGVSpc.3148_3150delCTAinsGTTp.Leu1050Val

Exon rankN/A

missense

Prot: ENSP00000428268.2UniProt: O60610-3

DIAPH1 ENST00000647433.1

HGVSc / HGVSpc.3175_3177delCTAinsGTTp.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 ACGS-UK Somatic Oncogenicity v2025

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