rs199749212

Variant names:

• chr5-141573626-G-A
• rs199749212
• NM_005219.5:c.2224C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-141573626-G-A
• chr5-141573626-G-C

Variant summary

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

The NM_005219.5(DIAPH1):​c.2224C>T​(p.Pro742Ser) variant causes a missense change. 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. P742A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 28)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09
• 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: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	NM_005219.5	MANE Select	c.2224C>T	p.Pro742Ser	missense	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.2197C>T	p.Pro733Ser	missense	Exon 15 of 27	NP_001073280.1
	DIAPH1	NM_001314007.2		c.2224C>T	p.Pro742Ser	missense	Exon 16 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.2224C>T	p.Pro742Ser	missense	Exon 16 of 28	ENSP00000373706.4
	DIAPH1	ENST00000518047.5	TSL:5	c.2197C>T	p.Pro733Ser	missense	Exon 15 of 27	ENSP00000428268.2
	DIAPH1	ENST00000647433.1		c.2224C>T	p.Pro742Ser	missense	Exon 16 of 29	ENSP00000494675.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.58
Sift	Benign	0.61	T
Sift4G	Uncertain	0.030	D
Polyphen		0.97	D
Vest4		0.30
MutPred		0.50		Gain of phosphorylation at P742 (P = 0.0023)
MVP		0.96
MPC		0.12
ClinPred		0.93	D
GERP RS		4.5
Varity_R		0.074
gMVP		0.27
Mutation Taster		=76/24	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: rs199749212; hg19: chr5-140953193;