chr5-141527671-G-T

Variant names:

• chr5-141527671-G-T
• rs200394036
• NM_005219.5:c.3175C>A
• DIAPH1 p.Leu1059Ile

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4

The NM_005219.5(DIAPH1):c.3175C>A (p.Leu1059Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000751 (AC=10) in the gnomAD database across 1,331,682 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000498. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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)

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000075 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000498 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	DIAPH1 NM_005219.5	MANE Select	c.3175C>A p.Leu1059Ile	missense	Exon 24 of 28	Prot: NP_005210.3
	DIAPH1 NM_001079812.3		c.3148C>A p.Leu1050Ile	missense	Exon 23 of 27	Prot: NP_001073280.1 UniProt:
	DIAPH1 NM_001314007.2		c.3175C>A p.Leu1059Ile	missense	Exon 24 of 29	Prot: NP_001300936.1 UniProt:

DIAPH1 NM_005219.5

MANE Select

HGVSc / HGVSpc.3175C>Ap.Leu1059Ile

Exon rankExon 24 of 28

missense

Prot: NP_005210.3

DIAPH1 NM_001079812.3

HGVSc / HGVSpc.3148C>Ap.Leu1050Ile

Exon rankExon 23 of 27

missense

Prot: NP_001073280.1UniProt: O60610-3

DIAPH1 NM_001314007.2

HGVSc / HGVSpc.3175C>Ap.Leu1059Ile

Exon rankExon 24 of 29

missense

Prot: NP_001300936.1UniProt: A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	DIAPH1 ENST00000389054.8	TSL:5MANE Select	c.3175C>A p.Leu1059Ile	missense	Exon 24 of 28	Prot: ENSP00000373706.4 UniProt:
	DIAPH1 ENST00000518047.5	TSL:5	c.3148C>A p.Leu1050Ile	missense	Exon 23 of 27	Prot: ENSP00000428268.2 UniProt:
	DIAPH1 ENST00000647433.1		c.3175C>A p.Leu1059Ile	missense	Exon 24 of 29	Prot: ENSP00000494675.1 UniProt:

DIAPH1 ENST00000389054.8

TSL:5MANE Select

HGVSc / HGVSpc.3175C>Ap.Leu1059Ile

Exon rankExon 24 of 28

missense

Prot: ENSP00000373706.4UniProt: O60610-1

DIAPH1 ENST00000518047.5

TSL:5

HGVSc / HGVSpc.3148C>Ap.Leu1050Ile

Exon rankExon 23 of 27

missense

Prot: ENSP00000428268.2UniProt: O60610-3

DIAPH1 ENST00000647433.1

HGVSc / HGVSpc.3175C>Ap.Leu1059Ile

Exon rankExon 24 of 29

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00	AC:0	Hom:0	AN:138292	Cov:28
GnomAD4 exome	AF: 0.00000751	AC:10	Hom:0	AN:1331682	Cov:38
GnomAD4 genome Warning	AF: 0.00	AC:0	Hom:0	AN:138292	Cov:28

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Benign	0.070
GPN-Star LLR	N/A	-7.1
GPN-Star score	N/A	7.1
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	72/28	polymorphism
MutationAssessor	Benign	1.9	M
PhyloP100	Benign	1.9
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.13
VESM-3B	Benign	-7.4

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs200394036;

hg19: chr5-140907238;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar