chr5-141527619-A-G

Variant names:

• chr5-141527619-A-G
• rs143763573
• NM_005219.5:c.3227T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005219.5(DIAPH1):​c.3227T>C​(p.Phe1076Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. F1076C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.25
• Publications: 5 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: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.3227T>C	p.Phe1076Ser	missense	Exon 24 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3200T>C	p.Phe1067Ser	missense	Exon 23 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.3227T>C	p.Phe1076Ser	missense	Exon 24 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.3227T>C	p.Phe1076Ser	missense	Exon 24 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.3200T>C	p.Phe1067Ser	missense	Exon 23 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.3227T>C	p.Phe1076Ser	missense	Exon 24 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.39
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.50		Gain of phosphorylation at F1076 (P = 0.0309)
MVP		0.51
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.52
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143763573; hg19: chr5-140907186;