5-141527671-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

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 frequency of 0.00000751 in 1,331,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. L1059V) has been classified as Likely benign.

• 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, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3709237).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. 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
	DIAPH1	NM_005219.5	MANE Select	c.3175C>A	p.Leu1059Ile	missense	Exon 24 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3148C>A	p.Leu1050Ile	missense	Exon 23 of 27	NP_001073280.1
	DIAPH1	NM_001314007.2		c.3175C>A	p.Leu1059Ile	missense	Exon 24 of 29	NP_001300936.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 138292 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000751 AC: 10 AN: 1331682 Hom.: 0 Cov.: 38 AF XY: 0.00000754 AC XY: 5 AN XY: 663140

African (AFR) AF: 0.00 AC: 0 AN: 29478

American (AMR) AF: 0.00 AC: 0 AN: 41814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23212

East Asian (EAS) AF: 0.00 AC: 0 AN: 33668

South Asian (SAS) AF: 0.00 AC: 0 AN: 80370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4880

European-Non Finnish (NFE) AF: 0.00000985 AC: 10 AN: 1015480

Other (OTH) AF: 0.00 AC: 0 AN: 53888

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 138292 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 66036

African (AFR) AF: 0.00 AC: 0 AN: 36268

American (AMR) AF: 0.00 AC: 0 AN: 13112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4692

South Asian (SAS) AF: 0.00 AC: 0 AN: 4426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66044

Other (OTH) AF: 0.00 AC: 0 AN: 1842

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.54		Loss of ubiquitination at K1057 (P = 0.0613)
MVP		0.56
MPC		1.3
ClinPred		0.95	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.17
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs200394036; hg19: chr5-140907238;